2-fluorofucosyl-N-aroylglucosamine derivatives, intermediates, therefor, and processes for producing these

ABSTRACT

2-Fluorofucosyl-N-aroylglucosamine derivatives which are obtained by substitution of a hydroxyl group at the 3- or 4-position of N-aroylglucosamine with 2-fluorofucose, their intermediates and preparation methods thereof. The 2-fluorofucosyl-N-aroylglucosamine derivatives which are useful medicinal components for the treatment, improvement and prevention of inflammation and diseases accompanying inflammation, their intermediates and preparation methods thereof can be provided.

This application is a 371 of PCT/JP98/03224 filed Jul. 16, 1998.

FIELD OF THE INVENTION

The present invention relates to 2-fluorofucosyl-N-aroylglucosaminederivatives which are obtained by substituting the hydroxyl group at the2-position with a fluorine atom in L-fucose of fucosyl-α-(1→3 or1→4)-N-aroylglucosamine which are derivatives of Lewis X, Lewis a,sialyl Lewis X or sialyl Lewis a glycosides (or saccharides) known asthe causal substances of inflammation or thrombus formation accompaniedby inflammation, tissular disorder due to infiltration of inflammatorycells, asthma, rheumatism, autoimmune disease, or cancer metastasis, andtheir intermediates, and preparation methods thereof (herein, the aroylgroup is synonymous with the arylcarbonyl group). Such derivatives areuseful as medicinal components for the purpose of treatment, improvementand prevention of the said diseases.

PRIOR ART

Sialyl Lewis X glycoside, which is a oligosaccharide including fucose,has been attracting attention in recent years as a molecule involved ina homing phenomena, where leucocytes interact with selecting, anadhesion-factor on vascular endothelial cells, and are expelled from thevascular system when inflammation occurs. Further, it has beenunderstood that another ligand of selectin, sialyl Lewis a glycoside[structural formula (IV)] is significantly involved in the livermetastasis of colon cancer [refer to Katsumoto Ito, Progress of MedicalScience; 179, 223 (1996)]. Some of the above homing phenomena areinitiated by the interaction between the lectinic cell-adhesion moleculecalled selectin and sialyl Lewis X oligosaccharide. Therefore,neutrophil (a kind of leukocyte)-dependent and selectin-dependent acuteinflammation is expected to be suppressed if sialyl Lewis Xoligosaccharide can be utilized as a selectin inhibitor.

As an example, a group at Michigan University showed that acuteinflammation of the lung induced experimentally in rats using cobratoxin was reduced by administering sialyl Lewis X glycoside [structuralformula (III)] [M. S. Mulligan et al., Nature 364, 149 (1993)], andHayashi et al. also reported the efficacy of sialyl Lewis X derivativesin a lung disease model [Shinichiro Tojo et al., Cell 29 (2), 17(1997)]. Further, various sialyl Lewis X derivatives have beensynthesized from the entirely novel point of view of developing drugsfor the inhibition of cell-adhesion. Among them interrelations betweentheir structures and activities have been investigated by Hasegawa andKiso et al. and their core partial structures are reportedly (1)carboxylic acid in sialic acid, (II) fucose residue, and (III) hydroxylgroups at the 4- and 6-positions in galactose [A. Hasegawa et al.,Carbohydrate Research; 257, 67 (1994)]. Furthermore, it is reported thatthe adhesion-inhibitory activity of the glycoside deoxidized at the1-position of the reducing terminal [structural formula (V)] to Pselectin, which is a member of the selectin family, is 20 times higherthan the activity of the sialyl Lewis X glycoside shown in StructuralFormula (III) [H. Kondo et al., Journal of Medicinal Chemistry 39, 1339(1996)]. In addition, synthesis of the Lewis X derivatives [structuralformula (VI)] by substituting a sialic acid moiety of sialyl Lewis Xwith an acidic functional group such as a sulfate residue, a phosphateresidue, or a carboxylic acid, and investigation of theadhesion-inhibitory activity for selectins lead to the discovery ofGSC-150 as a powerful selectin blocker [refer to H. Kondo et al.,Journal of Medicinal Chemistry 39, 2055 (1996); U.S. Pat. No. 5,589,465;JP Opening No. 8-99989]. ##STR1##

OBJECTS OF THE INVENTION

Lewis X or Lewis a derivatives are known as ligand moieties of Pselectin or L selectin that act as cell-adhesion molecules. Althoughthey are important compounds that function as cell recognition factorswhich specifically express these selecting, they are expected to easilylose their activity due to α-fucosidase existing in the human body,because they have an L-fucosyl-α-(1→3 or 1→4)-glucose skeleton [C. H.Wong et al., Journal of Organic Chemistry, 60, 3100 (1995)]. As afurther example, the following items 1-3 have been investigated from thestandpoint of selectin-adhesion-inhibitory activity or metabolicstability.

1. According to the previous application by the present inventors (JPAppl. 9-52902), sialyl Lewis X ganglioside was synthesized bysubstituting the hydroxyl group at the 2-position in fucose with afluorine atom in anticipation of improved metabolic stability toα-fucosidase, and it was found to have a similarselectin-adhesion-inhibitory activity as natural type sialyl Lewis Xganglioside. The following are typical compounds. ##STR2##

2. Hayashi et al. [M. Hayashi et al., Journal of Organic Chemistry; 61,2938 (1996); WO 96/20204] report that selectin-adhesion-inhibitoryactivity is enhanced by conversion of an acetylamide moiety of sialylLewis X into naphthoylamide. The following are typical compounds.##STR3## M. Hyashietal. Journal of Organic Chemistry; 61, 2938(1996).##STR4## M. Hayashi et al. WO 96/20204.

3. S. A. DeFrees et al. report that selectin-adhesion-inhibitoryactivity is enhanced by conversion of an acetylamide of theN-acetylglucosamine moiety in sialyl Lewis X into aroylamide [S. A.DeFrees et al,. Journal of Medicinal Chemistry; 39, 1357 (1996), WO94/26760, U.S. Pat. No. 5,604,207]. Further, they report that theadhesion-inhibitory activity was markedly enhanced by preparing sialylLewis X liposom where PEG-DSPE was integrated into the aroyl group [S.A. DeFrees et al., Journal of American Chemical Society; 118, 6101(1996)]. Examples are given as follows. ##STR5## S. A. DeFrees et al,.Journal of Medicinal Chemistry; 39, 1357 (1996). S. A. DeFrees et al.,WO 94/26760, S. A. DeFrees et al., U.S. Pat. No. 5,604,207. ##STR6## S.A. DeFrees et al., Journal of American Chemical Society; 118, 6101(1996)

Thus, sialyl Lewis X derivatives are considered to be practical, andproviding them is extremely meaningful. However, there is as yet nomethod for selectively α-2-fluorofucosylizing the 3- or 4-position inN-aroylgulucosamine derivatives. Moreover, these N-aroylglucosaminederivatives which are selectively α-2-fluorofucosylized at the 3- or4-positions are considered to be more efficient inselectin-adhesion-inhibitory activity and metabolic stability.Therefore, the present inventors have tried to create N-aroylglucosaminederivatives (fucosylglucosamine analogs) in which the 3- or 4-positionsare selectively α-2-fluorofucosylized as glycosides having more powerfulselectin-adhesion-inhibitory activity and greater metabolic stability.

OBJECTS OF THE INVENTION

The objects of the present invention are to provide2-fluorofucosyl-N-aroylglucosamine derivatives that have a superiorinhibitory activity to selectin-adhesion and greater metabolicstability, their intermediates, and preparation methods thereof.

CONSTITUTION OF THE INVENTION

Considering the prior situation described above and after extensivestudies, the present inventors have succeeded in synthesizing the LewisX and Lewis (a) analogs which are obtained by substituting the hydroxylgroup at the 3-position or 4-position in N-aroylglucosamines with2-fluorofucose, which strongly inhibits the adhesion between selectinsand neutrophils and which has greater metabolic stability.

Namely, the present invention relates to the2-fluorofucosyl-N-aroylglucosamine derivatives (hereinafter, sometimesreferred to as "the present inventive derivatives") represented by thefollowing general formula (1). ##STR7## [wherein X and Y in the abovegeneral formula (1) are a group represented by the following generalformula (A) or (B):

Y=general formula (B) when X=general formula (A); and

Y=general formula (A) when X=general formula (B)]. ##STR8## Herein, R inabove general formula (A) is a hydrogen atom, protecting group of thehydroxyl group, phosphate residue, sulfate residue, or the sialyl grouprepresented by the following general formula (a). ##STR9## (wherein R⁶in the above general formula (a) shows a hydrogen atom, sodium atom orC1-10 alkyl group; R⁷ shows a hydrogen atom, C1-10 alkanoyl group orC7-15 aroyl group; R⁸ shows an acetyl group, hydroxyacetyl group, orC1-10 alkanoyloxyacetyl group). Further, in the above general formula(1), R¹ is a hydrogen atom, hydroxyl group, C1-10 alkanoyloxy grouphaving no substituent or having one or more substituents, C7-15 aroyloxygroup, arylthio group having no substituent or having one or moresubstituents, C1-18 alkoxy group, branched long chain alkoxy group,arylmethoxy group having no substituent or having one or moresubstituents, 2-trisilylethoxy group having C1-4 alkyl group or phenylgroup, or a group represented by the following general formula (b) or(c). ##STR10## (wherein R⁹ in the above general formulas (b) and (c)shows a hydrogen atom, C1-10 alkanoyl group, C7-15 aroyl group orphenylmethoxy group having no substituent or having substituents; R¹⁰shows a hydrogen atom, hydroxyl group, 2-trisilylethoxy group havingC1-4 alkyl group or phenyl group, C1-30 alkoxy group, or a grouprepresented by the following general formula (d); R¹¹ shows a hydrogenatom or --O--C(═NH)CCl₃.) ##STR11## [wherein R¹² in the above generalformula (d) shows a hydrogen atom or benzoyl group; R¹³ shows an azide,amine or sphingosine represented by NHCO R¹⁴ (R¹⁴ is a C15-25 alkylgroup); R¹¹ shows hydrogen atom or --O--C(═NH)CCl₃ ]. Further, in theabove general formulas (1), (A) and (B), R², R³ and R⁴ are a hydrogenatom, C1-10 alkanoyl group, C7-15 aroyl group, or phenylmethyl grouphaving no substituent or having substituents (wherein at least two ofR², R³ and R⁴ may be the same as each other or they may be different)and R⁵ shows an aroyl group having no substituent or havingsubstituents. Furthermore, the present invention provides a preparationmethod for 2-fluorofucosyl-N-aroylglucosamine derivatives (hereinafter,sometimes referred to as "the preparation method of the presentinventive derivatives") using the compounds represented by the followinggeneral formulas (A') and (B') and the aroylglucosamine derivativesrepresented by the following general formula (C') as the method forpreparing the present inventive derivatives with good reproductivity.##STR12## (wherein R, R¹, R², R³, R⁴ and R⁵ in the above generalformulas (A'), (B') and (C') are the same as described above; R¹⁷, R¹⁸,R¹⁹ and R²⁰ are reactive groups, respectively; R¹⁷ shows reactivity withR¹⁹ or R²⁰ ; and R¹⁶ shows reactivity with R¹⁹ or R²⁰. Further, thepresent invention provides the intermediates tie of2-fluorofucosyl-N-aroylglucosamine derivatives (hereinafter, sometimesreferred to as "the first intermediate of the present invention")represented by the following general formula (4) as a useful syntheticintermediate of 2-fluorofucosyl-N-aroylglucosamine derivatives (namely,the Lewis X derivative, the present inventive derivatives) representedby the above general formula (1). ##STR13## (wherein R¹ and R² in theabove general formula (4) are the same as described above or in claim 1;R¹⁵ shows a phenyl group having no substituent or having substituents;and R¹⁶ shows an aroyl group having no substituent or havingsubstituents). Further, the present invention provides the intermediatesof 2-fluorofucosyl-N-aroylglucosamine derivatives (hereinafter,sometimes referred to as "the second intermediate of the presentinvention") represented by the following general formula (5) as a usefulsynthetic intermediate of 2-fluorofucosyl-N-aroylglucosamine derivatives(namely, the Lewis X derivative, the present inventive derivatives)represented by the above general formula (1). ##STR14## (wherein R¹, R²and R⁴ in the above general formula (5) are the same as described aboveor in claim 1, and R¹⁶ is the same as described above or in claim 15).Further, as the method for preparing the intermediates of2-fluorofucosyl-N-aroylglucosamine derivatives (the first intermediateof the present invention) represented by the above general formula (4)with good reproductivity, the present invention provides a method forpreparing the intermediate of 2-fluorofucosyl-N-aroylglucosaminederivatives (hereinafter, sometimes referred to as "the method forpreparing the first intermediate of the present invention") by reactingthe aroylglucosamine derivatives represented by the following generalformula (i) with the compound represented by the above general formula(B'). ##STR15## (wherein R¹, R¹⁵ and R¹⁶ in the above general formula(i) are the same as described above or in claim 15, and R²⁰ is the sameas described above or in claim 8). Further, as the method for preparingthe intermediates of 2-fluorofucosyl-N-aroylglucosamine derivatives(namely, the second intermediate of the present invention) representedby the above general formula (5) with good reproductivity, the presentinvention also provides a method for preparing the intermediate of the2-fluorofucosyl-N-aroylglucosamine derivatives (hereinafter, sometimesreferred to as "the method for preparing the second intermediate of thepresent invention") by cleaving a benzylidene ring of the intermediateof the 2-fluorofucosyl-N-aroylglucosamine derivatives represented by theabove general formula (4). However, the concept represented by "thederivatives" includes the salts in the context of the present inventivederivatives, their intermediates (the first intermediate and the secondintermediate of the present invention) and also these preparationmethods (the method for preparing the present inventive derivatives andthe method for preparing the first intermediates and the secondintermediates of the present invention: hereinafter, sometimes referredto as merely "the present invention" as a general term).

EMBODIMENT OF THE PRESENT INVENTION

The derivatives of the present invention are particularly preferably the2-fluorofucosyl-α-(1→3)-N-aroylglucosamine derivatives (or their salts)represented by the following general formula (2). ##STR16## (wherein Rin the above general formula (2) is a hydrogen atom, protecting group ofthe hydroxyl group, phosphate residue, sulfate residue or sialyl grouprepresented by the following general formula (a'). ##STR17## (wherein R⁸in the above general formula (a') shows an aliphatic acyl group). Inaddition, R¹ in the above general formula (2) is a hydrogen atom,hydroxyl group, C1-18 alkanoyloxy group having no substituent or havingat least one of the following substituents, C7-15 aroyloxy group, C1-10alkylthio group, arylthio group having no substituent or having the saidone or more substituents, C1-18 alkoxy group, branched long chain alkoxygroup, arylmethoxy group having no substituent or having the said one ormore substituents, 2-trisilylethoxy group having C1-4 alkyl group orphenyl group or a group represented by the following general formula(b') or (c'). ##STR18## (wherein R¹⁰ in the above general formulas (b')and (c') is a hydrogen atom, hydroxyl group, 2-trisilylethoxy grouphaving C1-4 alkyl group or phenyl group, C1-30 alkoxy group, orsphingosine represented by the following general formula (d'); and R¹¹is a hydrogen atom. ##STR19## [(wherein R¹³ in the above general formula(d') shows an azide, amine or NHCO R⁴ ; and the said R¹⁴ shows C15-25alkyl group). Herein, in the event that the said R¹ has two or more saidsubstituents in the above general formula (2), these substituents may bedifferent from each other. These substituents are at least one groupselected from the group comprising a halogen atom, trifluoromethylgroup, hydroxyl group, C1-18 alkoxy group, aryloxy group, aryl grouphaving a C1-10 alkyloxy group, amino group, aryl group having a C1-10alkylamino group, monoamino group having a C1-18 alkyl group, diaminogroup having a C1-18 alkyl group, amino group having C1-18 alkyl groupand C1-10 arylalkyl group, C1-18 alkanoylamino group, C7-15 aroylaminogroup, monocarbamoyl group having a C1-18 alkyl group, dicarbamoyl grouphaving a C1-18 alkyl group, arylcarbamoyl group having a C1-10 alkylgroup, carbamoyl group having a C1-18 alkyl group and a C1-10 arylalkylgroup, arylcarbamoyl group, C1-18 alkanoyl group, C7-15 aroyl group,C1-18 alkylthio group, arylthio group, C1-18 alkylsulfonyl group,arylsulfonyl group, cyano group and nitro group.

Herein, the groups substituted one or two times on the alkyl chains oron the aryl rings of the above substituents are also included in thesaid substituents. In addition, R⁵ is an aroyl group having nosubstituent or having substituents. Further, the derivatives of thepresent invention may be 2-fluorofucosyl-α-(1→3)-N-aroylglucosamiederivatives (or their salts) represented specifically by the followinggeneral formula (3). ##STR20## (wherein R and R⁵ in the above generalformula (3) are the same as described above, R¹ is a hydrogen atom,hydroxyl group, C1-10 alkanoyloxy group having no substituent or havingat least one of the said substituents, C7-15 aroyl group, C1-10alkylthio group, arylthio group having no substituent or having the saidone or more substituents, C1-18 alkoxy group, branched long chain alkoxygroup, arylmethoxy group having no substituent or having the said one ormore substituents, or 2-trisilylethoxy group having C1-4 alkyl group orphenyl group or a group represented by the following general formula(b') or (c'). ##STR21## [wherein R¹⁰ in the above general formulas (b')and (c') is a hydrogen atom, hydroxyl group, 2-trisilylethoxy grouphaving a C1-4 alkyl group or a phenyl group, C1-30 alkoxy group orsphingosine represented by the following general formula (d'); and R¹¹is a hydrogen atom. ##STR22## [(wherein R¹³ in the above general formula(d') shows an azide, amine or NHCO R¹⁴, and the said R¹⁴ shows a C15-25alkyl group). Herein, in the event that the said R¹ has the said two ormore substituents in the above general formula (3), these substituentsmay be different from each other. Further, the said substituents are thesame as described above and the groups substituted one or two times withthe said substituents on the alkyl groups or on the aryl rings of theabove substituents are also included in the said substituents. Further,as for the second intermediate of the present invention, the compoundrepresented by the following general formula (5') is preferable.##STR23## (wherein R² and R⁴ in the said general formula. (5') may bethe same or different from each other and show a hydrogen atom, C1-18alkanoyl group, C7-15 aroyl group, or phenylmethyl group having nosubstituent or having substituents. In addition, R⁵ shows the same asdescribed above. Further, R¹ is a hydrogen atom, hydroxyl group, C1-18alkanoyl group having no substituent or having at least one of the saidsubstituents, C7-15 aroyl group, C1-10 alkylthio group, arylthio grouphaving no substituent or having the said one or more substituents, C1-10alkoxy group, branched long chain alkoxy group, arylmethoxy group havingno substituent or having the said one or more substituents,2-trisilylethoxy group having a C1-4 alkyl group or phenyl group or agroup represented by the following general formula (b) or (c). ##STR24##[wherein R⁹ in the general formulas (b) and (c) shows a hydrogen atom,C1-18 alkanoyl group, C7-15 aroyl group, phenylmethoxy group having nosubstituent or having substituents; and R¹⁰ is a hydrogen atom, hydroxylgroup, 2-trisilylethoxy group having a C1-4 alkyl group or a phenylgroup, C1-30 alkoxy group or sphingosine represented by the followinggeneral formula (d); and R¹¹ is a hydrogen atom. ##STR25## [(wherein R¹²in the above general formula (d) shows a hydrogen atom or benzoyl group;R¹³ shows an azide, amine or NHCO R¹⁴ ; and the said R¹⁴ shows a C15-25alkyl group). Herein, in the event that the said R¹ has the said two ormore substituents in the above general formula (5'), these substituentsmay be different from each other. Herein, the said substituents are thesame as described above. In addition, for the first intermediate of thepresent invention, the compound represented principally by the followinggeneral formula (4') is preferable. ##STR26## [wherein R¹⁵ in the saidgeneral formula (4') shows a phenyl group having no substituent orhaving substituents, and Z shows a hydrogen atom or halogen atom (atleast two may be the same or they may all be different.); in addition,R¹ and R² are the same as described above]. Herein, as for the firstintermediate [said general formula (4)] and the second intermediate[said general formula (5)] of the present invention, the said R¹⁶ may beone group selected from the group of a phthalimide ring grouphereinafter, sometimes referred to as a "phthalimide group orphthalimide"), and a 2-naphthoylamide group and a 4-t-butylbenzoylamidegroup. Accordingly, the said R¹⁶ of the compound represented by the saidgeneral formula (i) which is a precursor of the first intermediate ofthe present invention is preferably the same substituent as theaforementioned substituent. Further, the ring moieties of these groupsmay be hydrogen-reduced moieties. Next, the substituents of the presentinvention are illustrated as follows. The alkyl group having C1-18 inthe said R¹ and substituents is a straight chained or a branched alkylgroup, and is also a cycloalkyl group, (cycloalkyl) alkyl group or(cycloalkyl) cycloalkyl group and the like. Specifically, they are asfollows: methyl group, ethyl group, propyl group, isopropyl group, butylgroup, isobutyl group, 2-butyl group, t-butyl group, pentyl group,3-pentyl group, isopentyl group, neopentyl group, hexyl group, heptylgroup, 4-heptyl group, octyl group, nonyl group, 5-nonyl group, decylgroup, undecyl group, 6-undecyl group, dodecyl group, tridecyl group,7-tridecyl group, tetradecyl group, pentadecyl group, 8-pentadecylgroup, hexadecyl group, heptadecyl group, 9-heptadecyl group, octadecylgroup, cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclopentylmethylgroup, cyclohexylmethyl group, (4-cyclohexyl) cyclohexyl group and thelike.

Further, the aryl group having a C1-10 alkyl group in the said R¹ andsubstituents is a C1-10 phenylalkyl group; for example, a straightchained or a branched C1-10 alkyl group having a phenyl group at theterminal position. Specifically, they are a benzyl group, phenethylgroup, phenylpropyl group, phenylbutyl group, phenylpentyl group,phenylhexyl group and the like. Further, the halogen atom in the saidsubstituents and the said Z is for example a fluorine atom, chlorineatom, bromine atom or iodine atom. Further, the C1-18 alkoxy group inthe said R¹ and the said substituents is a straight chain, a branchingor cyclic alkoxy group: specifically a methoxy group, ethoxy group,propoxy group, isopropoxy group, butoxy group, pentyloxy group,cyclopentyloxy group, hexyloxy group, cyclohexyloxy group, heptyloxygroup, octyloxy group, nonyloxy group, decyloxy group, undecyloxy group,dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxygroup, hexadecyloxy group, heptadecyloxy group, octadecyloxy group, andthe like.

In addition, the aryl in the said R¹ and the said substituents is formedby ring formation of any of a hydrocarbon, a hydrocarbon containing anoxygen atom, a hydrocarbon containing a sulfur atom, a hydrocarboncontaining a nitrogen atom, or a hydrocarbon containing two nitrogenatoms. This ring means an aromatic ring which is a five-membermonocyclic, a six-member monocyclic, a polycyclic fused ring fused froma six-member ring and a five-member ring, or a polycyclic fused ringfused from six-member rings. Namely, a monocyclic aromatic hydrocarbongroup such as a phenyl group is: for example, a polycyclic fusedaromatic hydrocarbon group such as a naphthyl group, anthracenyl group(anthryl group), or phenanthrenyl group; for example, aromaticheterocyclic groups such as a furyl group, thienyl group, pyridyl group,pyrazinyl group, benzofuranyl (benzo[b]furanyl) group, isobenzofuranyl(benzo [c] furanyl) group, benzothienyl (benzo[b]thienyl) group,isobezothienyl (benzo[c]thienyl) group, pyrimidinyl group, pyridadinylgroup, quinolinyl group, isoquinolinyl group, quinoxalinyl group,naphthilidinyl group, phthalazinyl group or quinazolinyl group, whichcontain an oxygen atom, a sulfur atom or one or two nitrogen atoms. Theposition of the binding branch in forming such groups can be optionallyselected from all possible positions. Further, a phenyl group ispreferable for the aryl group in the said R¹. In addition, the C1-18alkanoyl group in the said R¹, R², R⁴, R⁹ and the said substituents, orthe C1-18 alkanoyl, means a straight chained or a branched alkylcarbonylgroup or a cycloalkylcarbonyl group.

Specifically, they are a formyl group, acetyl group, propionyl group,butyryl group, isobutyryl group, valeryl group, isovaleryl group,pivaloyl group, pentanoyl group, isopentanoyl group, neopentanoyl group,hexanoyl group, heptanoyl group, octanoyl group, nonyl group, decanoylgroup, undecanoyl group, dodecanoyl group, hexadecanoyl group,heptadecanoyl group, octadecanoyl group, cyclopentanecarbonyl group,cyclohexanecarbonyl group and the like. Further, the C1-18 alkanoylaminogroup in the said substituents is synonymous with an alkylcarboxamidegroup having C1-18, and the example is an amino group substituted with astraight chained or branched C1-18 alkanoyl or a cycloalkyl carbonyl.Specifically, they are an acetylamino group, propionylamino group,butylylamino group, valerylamino group, pentanoylamino group,cyclopentylcarboxamide group, cyclohexylcarboxamide group,heptanoylamino group, octanoylamino group, nonanoylamino group,decanoylamino group, undecanoylamino group, dodecanoylamino group,tridecanoylamino group, tetradecanoylamino group, pentadecanoylaminogroup, hexadecanoylamino group, heptadecanoylamino group,octadecanoylamino group and the like. Herein, the said substituents maybe a monocarbamoyl group having a C1-18 alkyl group synonymous with amonoaminocarbonyl group having a C1-18 alkyl group, and the example is acarbonyl group substituted with a straight chain or branching alkylaminoor cycloalkylamino. Specifically, they are a methylcarbamoyl group,ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group,pentylcarbamoyl group, cyclopentylcarbamoyl group, hexylcarbamoyl group,cyclohexylcarbamoyl group, heptylcarbamoyl group, octylcarbamoyl group,nonylcarbamoyl group, decylcarbamoyl group, undecylcarbamoyl group,dodecylcarbamoyl group, tridecylcarbamoyl group, tetradecylcarbamoylgroup, pentadecylcarbamoyl group, hexadecylcarbamoyl group,heptadecylcarbamoyl group, octadecylcarbamoyl group, and the like.

Further, the dicarbamoyl group having a C1-18 alkyl group in the saidsubstituents is synonymous with a diaminocarbonyl group having a C1-18alkyl group, and the example is a dimethylcarbamoyl group,diethylcarbamoyl group and the like. Further, the groups substituted oneor two times with the said substituents on the alkyl chains or on thearyl rings of the said substituents are also included in the saidsubstituents. Namely, the groups specifically included in the saidsubstituents are as follows: 2-(2-ethoxyethoxy)-3-oxapentyloxy group,3,6-dioxaoctyloxy group, 3,6,9-trioxaundecyloxy group,3,4,5-trimethoxybenzyloxy group, 2-benzyloxyethoxy group,2-(3,4,5-trimethoxybenzyloxy)ethoxy group, 7-phenyl-3,6-dioxaheptyloxygroup, 2-hydroxyethoxy group,2-(2-hydroxyethoxy)-8-hydroxy-3,6-dioxaoctyloxy group,1,1-hydroxy-3,6,9-trioxaundecyloxy group, and the like. The positionsubstituted on the alkyl chains or on the aryl rings of the saidsubstituents is possible on all the carbon atoms except on the carbonatoms directly bonding to the oxygen atoms of the reduced terminals inglycosides.

These substituents can substitute not only for one position on the alkylchain or the aryl ring, but also for multiple position (especially 2-5).Further, in this case at least two of the kinds of substituents may bethe same or they may all be different. In addition, the aroyl grouphaving the substituents in the said R⁵ means an aroyl group(arylcarbonyl group) which has on aromatic rings one or multiplesubstituents of one or multiple kinds of the following substituents.These substituents can be halogen atom, nitro group, trifluoromethylgroup, a C1-18 alkyl group or a phenyl group including methyl group,ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,t-butyl group, pentyl group, 3-pentyl group, isopentyl group, neopentylgroup, hexyl group, heptyl group, 4-heptyl group, octyl group, nonylgroup, 5-nonyl group, decyl group, undecyl group, 6-undecyl group,dodecyl group, tridecyl group, 7-tridecyl group, tetradecyl group,pentadecyl group, 8-pentadecyl group, hexadecyl group, heptadecyl group,9-heptadecyl group, octadecyl group, cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group,cyclooctyl group, cyclopentylmethyl group, cyclohexylmethyl group,(4-cyclohexyl) cyclohexyl group, and the like. Substituents can be aC1-18 alkoxy group exemplified as follows: a methoxy group, ethoxygroup, propoxy group, butoxy group, pentyloxy group, cyclopentyloxygroup, hexyloxy group, cyclohexyloxy group, heptyloxy group, octyloxygroup, nonyloxy group, decyloxy group, undecyloxy group, dodecyloxygroup, tridecyloxy group, tetradecyloxy group, pentadecyloxy group,hexadecyloxy group, heptadecyloxy group, octadecyloxy group, and thelike.

Further, there can be a phenoxy group, benzyloxy group, benzyloxy groupwith substituents, amino group, benzylamino group, benzylamino groupwith substituents, C1-18 monoalkylamino group, each C1-18 dialkylaminogroup and alkylbenzylamino group with the C1-18 alkyl chain. The C1-18alkanoylamino group (alkylcarboxamide group) can be exemplified asfollows: an acetylamino group, propionylamino group, butylylamino group,valerylamino group, pentanoylamino group, cyclopentanecarboxamide group,hexanoylamino group, cyclohexanecarboxamide group, heptanoylamino group,octanoylamino group, nonanoylamino group, decanoylamino group,undecanoylamino group, dodecanoylamino group, tridecanoylamino group,tetradecanoylamino group, pentadecanoylamino group, hexadecanoylaminogroup, heptadecanoylamino group, octadecanoylamino group and the like.Further, there can be the C7-15 aroylamino group such as a benzoylaminogroup and a naphthoylamino group and the carboxyl group. Thesubstituents may be C1-18 alkylcarbamoyl group (alkylaminocarbonylgroup) in the alkyl chain are: for example, a methylcarbamoyl group,ethylcarbamoyl group, propylcarbamoyl group, butylcarbamoyl group,pentylcarbamoyl group, cyclopentylcarbamoyl group, hexylcarbamoyl group,cyclohexylcarbamoyl group, heptylcarbamoyl group, octylcarbamoyl group,nonylcarbamoyl group, decylcarbamoyl group, undecylcarbamoyl group,dodecylcarbamoyl group, tridecylcarbamoyl group, tetradecylcarbamoylgroup, pentadecylcarbamoyl group, hexdecylcarbamoyl group,heptadecylcarbamoyl group, octadecylcarbamoyl group, and the like.Further, other substituents are an arylcarbamoyl group, a C1-18alkylthio group, an arylthio group, a C1-18 alkylsulfonyl group, anarylsufonyl group, a cyano group, and the like. Further, the C1-10 alkylgroup in the said R⁶ is a straight chained or branched alkyl group andspecifically a methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, t-butyl group, pentyl group, 3-pentylgroup, isopentyl group, neopentyl group, hexyl group, and the like.Further, the C1-10 alkanoyl group or the C1-10 alkanoyl in the said R¹,R², R³, R⁴, R⁷, R⁸ and R⁹ is a straight chained or branched C1-10alkylcarbonyl, and the alkyl moiety may be substituted with one ormultiple halogen atoms and the like. Specifically, these substituentsare a formyl group, acetyl group, chloroacetyl group, dichloroacetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group, pivaloyl group, pentanoyl group, isopentanoyl group,neopentanoyl group and the like; specifically an acetyl group, achloroacetyl group, a trichloroacetyl group and the like are preferable.Further, the aroyl group or aroyl in the said R¹, R², R³, R⁴, R⁵, R⁷ andR⁹ is synonymous with an arylcarbonyl group, and the aryl moiety may bean aryl group having substituents such as described in the aryl grouprelating to the said R¹ and the said substituents.

Further, the phenylmethyl group having the substituents in the said R²,R³ and R⁴ means a benzyl group which has a halogen atom, a nitro group,an alkoxy group with 1-6 carbon atoms and the like on the phenyl ring,and specifically is a 4-fluorobenzyl group, 4-nitrobenzyl group,4-methoxybenzyl group or the like. Specifically the 4-methoxybenzylgroup is preferable. Further, the 2-trisilylethoxy group which has aC1-4 alkyl group or a phenyl group in the said R¹ and R¹⁰ means a2-silylethoxy group of which the same or different kinds of the C1-4alkyl group or the phenyl group are substituted for all three on thesilicon atom. Specifically, this is a 2-trimethylsilylethoxy group,2-triethylsilylethoxy group, 2-(triisopropylsilyl)ethoxy group,2-(t-butyldimethylsilyl)ethoxy group, 2-(triisopropylsilyl)ethoxy group,2-triphenylsilylethoxy group, 2-(t-butyldiethylsilyl)ethoxy group,2-(diphenylmethylsilyl)ethoxy group, 2-(t-butyldiphenylsilyl)ethoxygroup and the like. Further, the said R¹⁷ and R¹⁸ in the said generalformulas (A') and (B') are, for example: an acyloxy group and aroyloxygroup such as OAc and OBz; an alkylthio group and arylthio group such asSMe, SEt and SPh; an alkylsulfoxide group and arylsulfoxide group suchas S(O)Me, S(O)Et and S(O)Ph; a trichloroacetoimidate group representedby OC(═NH)CCl₃ ; a halogen atom represented by F, Br, Cl and I; a4-pentenyloxy group represented by O--(CH₂)₃ CH═CH₂ ; a phenylselenylgroup represented by SePh; a dialkylphosphate group and diarylphosphategroup such as O--P(O) (OMe)₂, O--P(O) (OEt)₂ and O--P(O) (OPh)₂ ; adialkylphophite group and a diarylphosphite group such as O--P(OMe)₂,O--P(OEt)₂ and O--P(OPh)₂ ; a diphenylphophineimidate group such asrepresented by O--P(═NTs)(NPh₂)₂ ; a tetramethylphosphoroamidate grouprepresented by O--P(O) (NMe₂)₂ and the like. Further, the said R¹⁹ andR²⁰ are, for example, a hydrogen atom, trialkylsilane group andtriarylsilane group such as SiMe₃, SiEt₃ and SiPh₃. Furthermore, thepresent inventive derivative [2-fluorofucosyl-α-(1→3 or1→4)-N-aroylglucosamine derivative] may, for example, form salts whichare sodium salts, lithium salts, potassium salts, magnesium salts andcalcium salts and the like. The above general formulas relatespecifically to 2-fluorofucosyl-α-(1→3 or 1→4)-N-aroylglucosaminederivatives represented, for example, by the following chemicalstructural formulas (α), (β), (γ) and (δ). Herein, "Ac" means an acetylgroup in the following formulas. Moreover, these compounds have not beenpublished in the literature yet and can provide derivatives whichexhibit excellent inhibitory activity to selectin adhesion and metabolicstability. ##STR27##

Next, the examples relating to the present inventive derivatives, theirintermediates and these preparation methods are illustrated. Thefundamental skeleton for the present inventive 2-fluorofucosyl-α-(1→3 or1→4)-N-aroylglucosamine derivative as a fluorine-substituted Lewis Xderivative comprises a galactose moiety, 2-fluorofucose moiety andN-aroylglucosamine moiety as understood from the said general formula(1) and the said structural formulas (α), (β), (γ) and (δ). Further, thepreparation of the present inventive derivatives, for example, includesthe methods wherein debenzylation is performed by catalyticallyhydrogenating the protected sialyl Lewis X derivative by the use ofPd--C/H₂, the resulting induction into the sialyl Lewis X derivativeaccording to the present invention which has the aroylamide in theglucosamine moiety. Such methods have been first found by the inventors.To avoid this catalytic reduction, an enzymatic method for synthesizingthe skeleton is known, for example, while according to the presentinvention, it is possible to obtain the sialyl Lewis X derivativecontaining an aroylglucosamine by a non-enzymatic method. First, the2-fluorofucosyl-α-(1→3)-N-aroylglucosamine derivative represented by thesaid structural formulas (α) and (β) is illustrated. For thisderivative, an example of a method for preparing a newfluorine-containing fucosylglucosamine lactoside derivative is asfollows. First, the compound represented by the following structuralformula (10) is synthesized followed by introduction into the compoundsrepresented by the following structural formulas (11) and (12). Then,reaction with a sialylgalactose moiety represented by the followingstructural formula (13) leads to the sialyl Lewis X glycoside[structural formula (14)]. Herein, "Bn" in the formulas means a benzylgroup and "Bz" means a benzoyl group (hereinafter, referred to as thesame). ##STR28## Catalytic reduction and acetylation of the compoundshown in structural formula (14) can lead to the sialyl Lewis Xglycoside derivative [structural formula (15)] in which the naphthalenemoiety is reduced. ##STR29## Continuously, deacetylation and alkalinehydrolysis can lead to the 2-fluorofucosyl-N-aroylgulucosaminederivative [structural formula (α)] can be obtained according to thepresent invention. ##STR30## In addition, the sialyl Lewis X glycosidederivative [structural formula (15)] can lead to a sialyl Lewis Xganglioside derivative by introducing a lipid, or so-called ceramide,according to the method described in the Journal of CarbohydrateChemistry; 10 (1991) 549-560. Moreover, the compound represented bystructural formula (10) can lead to the compound represented bystructural formulas (16) and (17), and after introducing thesialylgalactose [structural formula (13)], the sialyl Lewis X glycoside[structural formula (18)] can be obtained. ##STR31## By conductingcatalytic reduction, acetylation, deacetylation and alkaline hydrolysisof the compound represented by structural formula (18), the2-fluorofucosyl-N-aroylglucosamine derivative [structural formula (β)]according to the present invention can be prepared. ##STR32##

Next, the example of the preparation method for the2-fluorofucosyl-N-aroylglucosamine derivative,[2-fluorofucosyl-α-(1→3)-N-aroylglucosamine derivative] shown instructural formula (α) is illustrated, referring to the followingReaction Schemes 1 and 2. In this reactionprocess,2-(trimethylsikyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimid-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[said structural formula (e)] can be used as a starting material. Thiscompound can be synthesized according to the method described inCarbohydrate Research, 200 (1990) 269-285.

First, as shown in the following Reaction Scheme 1, by reacting methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bythe said structural formula (f) (for the preparation method: refer to JPOpening No. 9-052902) with the compound represented by the saidstructural formula (e) using dimethyl(methylthio)sulfonium triflate(DMTST)as a reaction promotor, the α-glycoside derivative [structuralformula (10)] can be obtained [reaction process (a)]. Next, afterdephthalimidation of this α-glycoside and subsequent 2-naphthoylation[structural formula (11)] [reaction process (b)], by performing areductive cleavage of the benzylidene group [structural formula (12)][reaction process (c)] and then introducing a sialylgalactose moiety[structural formula (13)] to (12) [reaction process (d)], the sialylLewis X hexose [structural formula (14): corresponding to generalformula (1) of the present invention] can be obtained. However, thecompound represented by the said (13) is the same as the compoundrepresented by the said structural formula (g) (hereinafter, refer tothe same). ##STR33##

Further, as shown in the following Reaction Scheme 2, by catalyticallyreducing the compound represented by structural formula (14) [reactionprocess (e)] followed by acetylation, the derivative of whichnaphthalene moiety is reduced [structural formula (15)] can be obtained.

Finally, one of the present objective compounds, which is represented bystructural formula (α), can, for example, be obtained by treating withsodium methoxide and sodium hydroxide [reaction process (f)]. ##STR34##In the reaction described above, although reduction of the naphthalenering takes place, by appropriately modifying the substituents R¹ and R⁴in general formula (1) and further changing the group represented bygeneral formula (B), it is possible to obtain a compound naphthalenemoiety of which is not reduced partially. For this reason, the said R¹may be ethyl-2,4,6-tri-O-acetyl-β-D-galactoside-3-oxyl group; the saidR⁴ may be acetyl groups and the said R² may be Bn for the said generalformula (B), for example. Next, the Reaction Schemes 1 and 2 are morespecifically illustrated. First, in the reaction process (a), bytreating 2-(trimethylsikyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (e)] with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside [strucuralformula (f)] in a reaction-inert solvent (e.g. benzene, toluene,methylene chloride or a mixture of these solvents) at 5° C.-10° C. for 2hr in the presence of an appropriate glycosylation catalyst (e.g.N-iodosuccinimide/scandium trifluoromethanesulfonate,N-iodosuccinimide/tetrabutylammonium triflate,dimethyl(methylthio)sulfonium triflate (DMTST),N-iodosuccinimide/trifluoromethanesulfonic acid, silvertrifluoromethanesulfonate/methylsulfenyl bromide and the like) andsynthetic zeolite (molecular sieves) etc., the reaction can lead to thefirst intermediate of the present invention which is the compoundrepresented by the following general formula (4'). Herein, the compoundrepresented by this general formula (4') is corresponding to thecompound represented by structural formula (10). ##STR35## [wherein R¹⁵in the said general formula (4') shows a phenyl group having nosubstituent or having substituents, Z comprises at least two identicalor all different groups selected from hydrogen atoms or halogen atoms,in addition, R¹ and R² are the same as described above]. Next, in thereaction process (b), removing the phthalimide of the glucosamine moietyby treating it in a reaction-inert solvent (e.g. benzene, toluene,methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran,dimethyl sulfoxide, dimethyl formamide, methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol or a mixture of these solvents) inthe presence of a deprotective agent for the phthalimide (e.g.hydrazine, ethylene diamine or their mixture) at 30° C.-100° C. for 6-24hr, without or after purification, by reacting 2-naphthoyl chloride withthe above product in the presence of a basic organic catalyst (e.g.dimethylaminopyridine, diethylaminopyridine,1,8-diazabicyclo[5,4,0]-7-undecene, 1,5-diazabicyclo[4,3,0]-5-nonene ortheir mixture, etc.) used as an acylation condition in a basic organicsolvent (e.g. trimethylamine, pyridine γ-lutidine, pyperidine,N-methylmorpholine, or a mixture of these solvents, etc.) at 5° C.-50°C., the above product can be converted to the resulting naphthoylatedform which is the compound (one of the first intermediates of thepresent invention) represented by structural formula (11).

Further, in the reaction process (c), by cleaving the benzylidene moietyof the compound represented by the said structural formula (11) using areductive cleaving reagent (e.g. sodium cyanoborohydride-hydrogenchloride, borane trimethylamine complex-aluminum chloride, boranedimethylamine complex-boron trifluoride ether complex and the like) in areaction-inert solvent (e.g. diethyl ether, tetrahydrofuran,acetonitrile, propionitrile, benzene, toluene, methylene chloride, or amixture of these solvents, etc.), the compound (one of the secondintermediate of the present invention) represented by structural formula(12) can be obtained. Furthermore, in the reaction process (d), becauseall hydroxyl groups of the glucosamine moiety in the compoundrepresented by structural formula (12) are protected with benzoyl groupsand the like, except the hydroxyl group at the 4-position, byintroducing sialylgalactose [structural formula (13)] in the presence ofthe said glycosylation accelerator, the resulting compound [which isincluded in the present inventive derivatives represented by generalformula (1)] represented by structural formula (14) can be obtained.This sialylgalactose can be introduced by treating it in areaction-inert solvent (e.g. benzene, toluene, methylene chloride,dichloroethane, diethyl ether, tetrahydrofuran, or a mixture of thesesolvents, etc.) at 5° C.-35° C. for 12-24 hr in the presence of anappropriate glycosylation accelerator (e.g. N-iodosuccinimide/scandiumtrifluoromethanesulfonate, N-iodosuccinimide/tetrabutylammoniumtriflate, dimethyl(methylthio)sulfonium triflate (DMTST),N-iodosuccinimide/trifluoromethanesulfonic acid, silvertrifluoromethanesulfonate/methylsulfenyl bromide and the like) andsynthetic zeolite (molecular sieves), etc.

Further, in the reaction process (e), by removing the benzyl group ofthe obtained sialyl Lewis X glycoside by reacting it in a reaction-inertsolvent (e.g. methanol, ethanol, n-propanol, isopropanol, ethyl acetate,methyl acetate, acetic acid or a mixture of these solvents, etc.) in thepresence of the catalysts for catalytic reduction (e.g.palladium--carbon, palladium hydroxide--carbon, palladium--bariumsulfate, etc.) using a hydrogen donor (e.g. hydrogen gas, cyclohexene,cyclohexadiene, formic acid, ammonium formate salts, etc.) at 0° C.-50°C. for 10-120 hr, and by acetylating the generated free hydroxyl groupin a basic organic solvent (e.g. pyridine, triethylamine, γ-lutidine,piperidine, N-methylmorpholine or a mixture of these solvents, etc.)using an acetylating agent (e.g. acetic anhydride, acetyl chloride, andthe like) at 0° C.-60° C. for 2-40 hr, the compound represented bystructural formula (15) can be obtained [which is included in thepresent inventive derivative represented by general formula (1)].Further, in the reaction process (f), by reacting benzoyl group (Bz) andacetyl group (Ac) as protective groups of a hydroxyl group with analkaline metal alkoxide or alkalineearthmetal alkoxide (e.g. sodiummethoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide,magnesium methoxide, calcium methoxide, and the like), or alkaline metalhydroxides and alkalineearthmetal hydroxides (e.g. sodium hydroxide,lithium hydroxide, potassium hydroxide, magnesium hydroxide, calciumhydroxide, and the like) in a protic solvent (e.g. water, methanol,ethanol, n-propanol, isopropanol, n-butanol, t-butanol or a mixture ofthese solvents, etc.) at 0° C.-40° C. for 2-48 hr, the compoundrepresented by structural formula (α) as2-fluorofucosyl-α-(1→3)-N-tetrahydronaphthylglucosamine derivativeaccording to the present invention can be obtained.

Further, the example method to prepare the present inventive derivativesrepresented by the above structural formula (β) are illustratedreferring to the following Reaction Schemes 3 and 4. In this reactionprocess, 2-(trimethylsikyl)ethylO-(2-deoxy-3,4-di-O-benzyl-2-fluoro-α-fucopyranosyl)-(1→3)-O-(4,6O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (10)] can be used as starting material. First, asshown in the following Reaction Scheme 3, after dephthalimidation of thecompound represented by structural formula (10), by4-t-butylbenzoylation [structural formula (16)] [reaction process (g)]followed by reductive cleavage of the benzylidene group [structuralformula (17)] [reaction process (h)], and introduction ofsialylgalactose moiety [structural formula (13)] into (17) [reactionprocess (i)], sialyl Lewis X hexose [structural formula (18)corresponding to general formula (1) of the present invention] can beobtained. ##STR36##

Further, as shown in the following Reaction Scheme 4, the derivative[structural formula (19)] can be obtained by catalytic reduction of thecompound represented by structural formula (18) [reaction process (i)]followed by acetylation. Finally, one of the object compoundsrepresented by structural formula (β) of the present invention can beobtained, for example, by treating with sodium methoxide, sodiumhydroxide and the like [reaction process (k)]. ##STR37## Next, theReaction Schemes 3 and 4 are illustrated in detail. First, in thereaction process (g), removing the phthalimide of the glucosamine moietyby treating the compound represented by structural formula (10) in areaction-inert solvent (e.g. benzene, toluene, methylene chloride,dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide,dimethyl formamide, methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol or a mixture of these solvents) in the presence ofa deprotective agent for the phthalimide (e.g. hydrazine, ethylenediamine or their mixture) at 30° C.-100° C. for 6-24 hr, without orafter purification, by reacting 4-t-butylbenzoyl chloride with the aboveproduct in the presence of a basic organic catalyst (e.g.dimethylaminopyridine, diethylaminopyridine,1,8-diazabicyclo[5,4,0]-7-undecene, 1,5-diazabicyclo[4,3,0]-5-nonene ortheir mixture, etc.) used as an acylation condition in a basic organicsolvent (e.g. trimethylamine, pyridine, γ-lutidine, pyperidine,N-methylmorpholine, or a mixture of these solvents, etc.) at 5° C.-50°C., the above product can be converted to the resulting4-t-butylbenzoylated form which is the compound (one of the firstintermediates of the present invention) represented by structuralformula (16). Further, in the reaction process (h), by cleaving thebenzylidene moiety of the compound represented by the said structuralformula (16) using a reductive cleaving reagent (e.g. sodiumcyanoborohydride-hydrogen chloride, borane trimethylaminecomplex-aluminum chloride, borane dimethylamine complex-borontrifluoride ether complex and the like) in a reaction-inert solvent(e.g. diethyl ether, tetrahydrofuran, acetonitrile, propionitrile,benzene, toluene, methylene chloride, or a mixture of these solvents,etc.), the compound (one of the second intermediates of the presentinvention) represented by structural formula (17) can be obtained.

Further, in the reaction process (i), because all hydroxyl groups of theglucosamine moiety in the compound represented by structural formula(17) are protected with benzoyl groups and the like, except the hydroxylgroup at the 4-position, by introducing sialylgalactose [structuralformula (13)] in the presence of the said glycosylation promotor, theresulting compound [which is included in the present inventivederivatives represented by general formula (1)] represented bystructural formula (18) can be obtained. This sialylgalactose can beintroduced by treating it in a reaction-inert solvent (e.g. benzene,toluene, methylene chloride, dichloroethane, diethyl ether,tetrahydrofuran, or a mixture of these solvents, etc.) at 5° C.-35° C.for 12-24 hr in the presence of an appropriate glycosylation promotor(e.g. N-iodosuccinimide/scandium trifluoromethanesulfonate,N-iodosuccinimide/tetrabutylammonium triflate,dimethyl(methylthio)sulfonium triflate (DMTST),N-iodosuccinimide/trifluoromethanesulfonic acid, silvertrifluoromethanesulfonate/methylsulfenyl bromide and the like) andsynthetic zeolite (molecular sieves), etc.)

Further, in the reaction process (j), by removing the benzyl group ofthe obtained sialyl Lewis X glycoside by reacting in a reaction-inertsolvent (e.g. methanol, ethanol, n-propanol, isopropanol, ethyl acetate,methyl acetate, acetic acid or a mixture of these solvents, etc.) in thepresence of a catalyst for catalytic reduction (e.g. palladium--carbon,palladium hydroxide--carbon, palladium--barium sulfate) using hydrogendonors (e.g. hydrogen gas, cyclohexene, cyclohexadiene, formic acid,ammonium formate salts, etc.) at 0° C.-50° C. for 10-120 hr, and byacetylating the generated free hydroxyl group in a basic organic solvent(e.g. pyridine, triethylamine, γ-lutidine, piperidine,N-methylmorpholine or a mixture of these solvents, etc.) using anacetylating agent (e.g. acetic anhydride, acetyl chloride, and the like)at 0° C.-60° C. for 2-40 hr, the compound represented by structuralformula (19) can be obtained [which is included in the present inventivederivative represented by general formula (1)]. Finally, in the reactionprocess (k), byreacting the benzoyl group (Bz) and acetyl group (Ac) asprotective groups of a hydroxyl group with an alkaline metal alkoxide oralkalineearthmetal alkoxide (e.g. sodium methoxide, sodium ethoxide,sodium t-butoxide, lithium methoxide, magnesium methoxide, calciummethoxide, and the like), or an alkaline metal hydroxide oralkalineearthmetal hydroxide (e.g. sodium hydroxide, lithium hydroxide,potassium hydroxide, magnesium hydroxide, calcium hydroxide, and thelike) in a protic solvent (e.g. water, methanol, ethanol, n-propanol,isopropanol, n-butanol, t-butanol or a mixture of these solvents, etc.)at 0° C.-40° C. for 2-48 hr, the compound represented by structuralformula (β) as 2-fluorofucosyl-α-(1→3)-N-4-t-butylbenzoylglucosaminederivative according to the present invention can be obtained. Next, the2-fluorofucosyl-α-(1→4)-N-aroylglucosamine derivative represented by theformulas (γ) and (δ) is illustrated as follows. After synthesizing thecompound represented by structural formula (21) from the compoundrepresented by structural formula (20) referring to the method describedin Carbohydrate Research, 200, 269-285 (1990), this derivative can beled to the compound represented by the said structural formula (γ) andthe compound represented by the said structural formula (δ) according tothe present invention.

Namely, after synthesizing the compound represented by structuralformula (21) referring to the Journal of Carbohydrate Chemistry, 13,641-654 (1994), the objective compounds of the present inventionrepresented by the said structural formulas (γ) and (δ) can be obtained.The compound represented by structural formula (21) can be obtained bydeacetylation, dephthalimidation and 2-naphthoylation of the knowncompound, 2-(trimethylsikyl)ethylO-(3,4,6-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (20)] as a starting material. Further, as shown instructural formula (22), after introduction of the benzylidene group,the compound represented by structural formula (23) can be obtained byreductive cleavage of this moiety. ##STR38## Further, in introducing thecompound which becomes the sialylgalactose moiety represented by thefollowing structural formula (13), silvertrifluoromethanesulfonate/methylsulfenyl bromide, for example, can beused. ##STR39## Furthermore, α-glycoside derivatives can be obtained byreaction of the only one remaining hydroxyl group with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside using, forexample, N-iodosuccinimide/trifluoromethanesulfonic acid as a reactionpromotor. Thus, sialyl Lewis a hexose (which corresponds to generalformula (1) of the present invention) represented by the followingstructural formula (24) can be obtained. In addition, catalyticreduction and acetylation of the compound represented by the saidstructural formula (24) can lead to the derivative represented bystructural formula (25) where the naphthalene moiety of the compound(24) is reduced. Finally, the 2-fluorofucosyl-N-aroylglucosaminederivative represented by structural formula (γ) which is one of theobjective compounds of the present invention can be obtained by treatingwith sodium methoxide, sodium hydroxide and the like. ##STR40## Further,the sialyl Lewis a glycoside represented by structural formula (25) canbe led to sialyl Lewis a ganglioside derivatives by introducing thelipid, a so-called ceramide, referring to the method described in theJournal of Carbohydrate Chemistry, 13, 641-654 (1994). Further, startingfrom the compound represented by structural formula (20), afterintroducing a benzylidene group [structural formula (27)] into thecompound represented by structural formula (26) which is obtained fromdeacetylation, dephthalimidation and 4-t-butylbenzoylation, by reductivecleavage of this moiety the compound represented by structural formula(28) can be obtained. ##STR41## Further, in introducing the compoundwhich becomes the sialylgalactose moiety represented by the followingstructural formula (13), silver trifluoromethanesulfonate/methylsulfenylbromide, for example, can be used. ##STR42## Furthermore, α-glycosidederivatives can be obtained by reaction of the only one remaininghydroxyl group with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside using, forexample, N-iodosuccinimide/trifluoromethanesulfonic acid as a reactionpromotor. Thus, sialyl Lewis a hexose (which corresponds to generalformula (1) of the present invention) represented by the followingstructural formula (29) can be obtained. In addition, catalyticreduction and acetylation of the compound represented by the saidstructural formula (29) can lead to the derivative represented bystructural formula (30) where its naphthalene moiety is reduced.Finally, the 2-fluorofucosyl-N-aroylglucosamine derivative representedby structural formula (δ) which is one of the objective compounds of thepresent invention can be obtained by treating with sodium methoxide,sodium hydroxide and the like. ##STR43## Further, the sialyl Lewis aglycoside represented by structural formula (30) can be led to sialylLewis a ganglioside derivatives by introducing the lipid, a so-calledceramide, referring to the method described in the Journal ofCarbohydrate Chemistry, 13, 641-654 (1994).

Next, the 2-fluorofucosyl-α-(1→4)-N-tetrahydronaphthylglucosaminederivative as shown in structural formula (γ) can be prepared by thereaction process as shown in the following Reaction Schemes 5 and 6. Inthis reaction process, 2-(trimethylsikyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (20)] can be used as a starting material. Thiscompound is synthesized by the method described in CarbohydrateResearch; 200, 269-285 (1990). The compound represented by the abovestructural formula (20) corresponds to the compound represented by theabove structural formula (h). First, as shown in the Reaction Scheme 5,after deacetylation and dephthalimidation of this compound [structuralformula (20)], this process comprises 2-naphthoylation of this compound[structural formula (21), reaction process (1)] followed by introductionof a benzylidene group [structural formula (22), reaction process (m)].Next, performing reductive cleavage of the benzylidene group [structuralformula (23), reaction process (n)], then introducing thesialylgalactose moiety represented by structural formula (13), andfinally by reacting with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside [reactionprocess (o)] using, for example,N-iodosuccinimide/trifluoromethanesulfonic acid as a reaction promotor,the sialyl Lewis a hexose [corresponding to the derivative representedby general formula (1) of the present invention] represented bystructural formula (24) can be obtained. ##STR44## In addition, as shownin the following Reaction Scheme 6, performing catalytic reduction[reaction process (p)] of the compound represented by structural formula(24) followed by acetylation, can lead to the derivative represented bystructural formula (25) where its naphthalene moiety is partiallyreduced. Finally, the derivative represented by structural formula (γ)which is one of the objects of the present invention, can be obtained bytreating with sodium methoxide, sodium hydroxide and the like [reactionprocess (q)]. ##STR45## Although the naphthalene ring is reduced in theabove reaction, it is possible to obtain the compound in which thenaphthalene moiety is not partially reduced by appropriately modifyingthe substituents R¹ and R⁴ in general formula (1) and also thesubstituents represented by general formula (B). For this purpose, thesaid R¹, R⁴ and R² in the case of general formula (B) may be modified toethyl-2,4,6-tri-O-acetyl-β-D-galactoside-3-oxyl group, acetyl group, andBn, respectively, similar to the above description. Next, the ReactionSchemes 5 and 6 are illustrated in detail. In this reaction process (1),acetyl groups of 2-(trimethylsilyl) ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (20)] as a starting material are removed using analkaline metal alkoxide or alkalineearthmetal alkoxide (e.g. sodiummethoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide,magnesium methoxide, calcium methoxide, and the like), or an alkalinemetal hydroxide or alkalineearthmetal hydroxide (e.g. sodium hydroxide,lithium hydroxide, potassium hydroxide, magnesium hydroxide, calciumhydroxide, and the like) in a protic solvent (e.g. water, methanol,ethanol, n-propanol, isopropanol, n-butanol, t-butanol or a mixture ofthese solvents, etc.) at 0° C.-40° C. for 2-48 hr.

Thereafter, after removing the phthalimide of the glucosamine moiety bytreatment in a reaction-inert solvent (e.g. benzene, toluene, methylenechloride, dichloroethane, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethyl formamide, methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol or a mixture of these solvents) inthe presence of a deprotective agent for the phthalimide (e.g.hydrazine, ethylene diamine or their mixture) at 30° C.-100° C. for 6-24hr, without or after purification, by reacting 2-naphthoyl chloride withthe above product in a reaction-inert solvent (e.g. benzene, toluene,methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran,dimethyl sulfoxide, dimethyl formamide, methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol or a mixture of these solvents) at 5°C.-50° C. for 2-24 hr, the above product can be converted to theresulting 2-naphthoylated form represented by structural formula (21).Further, in the reaction process (m), by introducing a in benzylidenegroup into the hydroxyl groups at the 4- and 6-positions of the compoundrepresented by the said structural formula (21), in the presence ofbenzaldehyde dimethylacetal/p-toluenesulfonic acid,benzaldehyde-anhydrous zinc chloride, benzaldehyde-conc. sulfuric acid,or the like, the compound represented by structural formula (22) can beobtained. Next, in the reaction process (n), after the compoundrepresented by structural formula (22) is obtained by introducing thesaid benzylidene group, by cleaving the said benzylidene group using areductive cleaving reagent (e.g. sodium cyanoborohydride-hydrogenchloride, borane trimethylamine complex-aluminum chloride, boranedimethylamine complex-boron trifluoride ether complex and the like) in areaction-inert solvent (e.g. benzene, toluene, methylene chloride,dichloroethane, diethyl ether, tetrahydrofuran, dimethyl sulfoxide,dimethyl formamide, methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol or a mixture of these solvents), the compoundrepresented by structural formula (23) can be obtained.

Next, in the reaction process (o), because all hydroxyl groups of theglucosamine moiety in the compound represented by structural formula(23) are protected with benzyl groups and the like except the twohydroxyl groups at the 3- and 4-positions, introducing sialylgalactose[structural formula (13)] and in turn methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside becomespossible. The sialyl Lewis a hexose represented by structural formula(24) (which corresponds to general formula (1) of the present invention)can be obtained by treatment in a reaction-inert solvent (e.g. benzene,toluene, methylene chloride, dichloroethane, diethyl ether,tetrahydrofuran, or a mixture of these solvents, etc.) at 5° C.-35° C.for 12-24 hr in the presence of an appropriate glycosylation promotor(e.g. N-iodosuccinimide/scandium trifluoromethanesulfonate,N-iodosuccinimide/tetrabutylammonium triflate,dimethyl(methylthio)sulfonium triflate (DMTST),N-iodosuccinimide/trifluoromethanesulfonic acid, silvertrifluoromethanesulfonate/methylsulfenyl bromide and the like) andsynthetic zeolite (molecular sieves), etc.

Next, in the reaction process (p), by removing the benzyl group of theobtained sialyl Lewis a glycoside by reaction in a reaction-inertsolvent (e.g. methanol, ethanol, n-propanol, isopropanol, ethyl acetate,methyl acetate, acetic acid or a mixture of these solvents, etc.) in thepresence of the catalysts for catalytic reduction (e.g.palladium--carbon, palladium hydroxide--carbon, palladium--bariumsulfate) using a hydrogen donor (e.g. hydrogen gas, cyclohexene,cyclohexadiene, formic acid, ammonium formate salts, etc.) at 0° C.-50°C. for 10-120 hr, and by acetylating the generated free hydroxyl groupin a basic organic solvent (e.g. pyridine, triethylamine, γ-lutidine,piperidine, N-methylmorpholine or a mixture of these solvents, etc.)using an acetylating agent (e.g. acetic anhydride, acetyl chloride, andthe like) at 0° C.-60° C. for 2-40 hr, the compound represented bystructural formula (25) can be obtained. Finally, in the reactionprocess (q), by reacting benzoyl (Bz) and acetyl groups (Ac) asprotective groups of the hydroxyl groups with an alkaline metal alkoxideor alkalineearthmetal alkoxide (e.g. sodiummethoxide, sodium ethoxide,sodium t-butoxide, lithium methoxide, magnesium methoxide, calciummethoxide, and the like), or an alkaline metal hydroxide andalkalineearthmetal hydroxide (e.g. sodium hydroxide, lithium hydroxide,potassium hydroxide, magnesium hydroxide, calcium hydroxide, and thelike) in a protic solvent (e.g. water, methanol, ethanol, n-propanol,isopropanol, n-butanol, t-butanol or a mixture of these solvents, etc.)at 0° C.-40° C. for 2-48 hr, the compound represented by structuralformula (γ) as 2-fluorofucosyl-α-(1→4)-N-tetrahydronaphthylglucosaminederivative of the present invention can be obtained.

Next, the preparation method for2-fluorofucosyl-α-(1→4)-N-4-t-butylbenzoyl-glucosamine derivativerepresented by the said structural formula (δ) is illustrated referringto the following Reaction Schemes 7 and 8. In this reaction process,2-(trimethylsikyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-o-benzyl-β-D-glucopyranoside[structural formula (20)] can be used as a starting material. First, asshown in the Reaction Scheme 7, after deacetylation anddephthalimidation of this compound [structural formula (20)], thisScheme comprises 4-t-butylbenzoylation of this compound [structuralformula (26), reaction process (r)] followed by introduction of abenzylidene group [structural formula (27), reaction process (s)]. Next,by performing reductive cleavage of the benzylidene group [structuralformula (28), reaction process (t)], then introducing thesialylgalactose moiety represented by structural formula (13) using, forexample, silver trifluoromethanesulfonate/methylsulfenyl bromide as areaction accelerator, and by reacting with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside [reactionprocess (u)] using, for example,N-iodosuccinimide/trifluoromethanesulfonic acid, the sialyl Lewis ahexose [corresponding to the derivative represented by general formula(1) of the present invention] represented by structural formula (29) canbe obtained. ##STR46## In addition, as shown in the following ReactionScheme 8, catalytic reduction [reaction process (v)] of the compoundrepresented by structural formula (29) followed by acetylation can leadto the derivative represented by structural formula (30) where itsnaphthalene moiety is partially reduced. Finally, the derivativerepresented by structural formula (δ) which is the objective compound ofthe present invention can be obtained by treating with sodium methoxide,sodium hydroxide and the like [reaction process (w)]. ##STR47## Next,Reaction Schemes 7 and 8 are further specifically illustrated. In thereaction process (r), 2-(trimethylsikyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside[structural formula (20)] as a starting material is deacetylated by theuse of an alkaline metal alkoxide or a alkalineearthmetal alkoxide (e.g.sodium methoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide,magnesium methoxide, calcium methoxide, and the like), or a alkalinemetal hydroxide or alkalineearthmetal hydroxide (e.g. sodium hydroxide,lithium hydroxide, potassiumhydroxide, magnesiumhydroxide,calciumhydroxide, and the like) in a protic solvent (e.g. water,methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol or amixture of these solvents, etc.) at 0° C.-40° C. for 2-48 hr.Thereafter, the phthalimide of the glucosamine moiety is removed bytreatment in a reaction-inert solvent (e.g. benzene, toluene, methylenechloride, dichloroethane, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethyl formamide, methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol or a mixture of these solvents) inthe presence of a deprotective agent of phthalimide (e.g. hydrazine,ethylene diamine or a mixture of these) at 30° C.-100° C. for 6-24 hr.Then, without or after purification, 4-t-butylbenzoylchloride is reactedwith the above product in a reaction-inert solvent (e.g. benzene,toluene, methylene chloride, dichloroethane, diethyl ether,tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol or a mixture ofthese solvents) at 5° C.-50° C. for 2-24 hr, and it can be converted tothe resulting 4-t-butylbenzoylated form represented by structuralformula (26). Further, in the reaction scheme (s), introduction of abenzylidene group into the hydroxyl groups at the 4- and 6-positions ofthe compound represented by the said structural formula (26), forexample, in the presence of benzaldehydedimethylacetal-p-toluenesulfonic acid, benzaldehyde-anhydrous zincchloride or benzaldehyde-conc. sulfuric acid can lead to the compoundrepresented by structural formula (27). Next, in the reaction process(t), after obtaining the compound represented by structural formula (27)by introducing the said benzylidene group, cleaving the said benzylidenemoiety using a reductive cleaving reagent (e.g. sodiumcyanoborohydride-hydrogen chloride, borane. dimethylaminecomplex-aluminum chloride, borane dimethylamine complex-borontrifluoride ether complex and the like) in a reaction-inert solvent(e.g. benzene, toluene, methylene chloride, dichloroethane, diethylether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol or a mixture ofthese solvents and the like) can lead to the compound represented bystructural formula (28). Next, in the reaction process (u), because allhydroxyl groups of the glucosamine moiety in the compound represented bystructural formula (28) are protected with benzyl groups and the likeexcept the two hydroxyl groups at the 3- and 4-positions of theglucosamine moiety, in turn introducing sialylgalactose [structuralformula (13)] and methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bythe said structural formula (f) becomes possible. In this reaction, thesialyl Lewis a hexose represented by structural formula (29) (whichcorresponds to general formula (1) of the present invention) can beobtained by treatment in a reaction-inert solvent (e.g. benzene,toluene, methylene chloride, dichloroethane, diethyl ether,tetrahydrofuran, or a mixture of these solvents, etc.) at 5° C.-35° C.for 12-24 hr in the presence of an appropriate glycosylation accelerator(e.g. N-iodosuccinimide/scandium trifluoromethanesulfonate,N-iodosuccinimide/tetrabutylammonium triflate,dimethyl(methylthio)sulfonium triflate (DMTST),N-iodosuccinimide/trifluoromethanesulfonic acid, silvertrifluoromethanesulfonate/methylsulfenyl bromide and the like) andsynthetic zeolite (molecular sieves), etc. Next, in the reaction process(v), the benzyl group of the sialyl Lewis a glycoside obtained as above,is removed by reaction in a reaction-inert solvent (e.g. methanol,ethanol, n-propanol, isopropanol, ethyl acetate, methyl acetate, aceticacid or a mixture of these solvents and the like) in the presence of acatalyst for catalytic reduction (e.g. palladium--carbon, palladiumhydroxide--carbon, palladium--barium sulfate) using a hydrogen donor(e.g. hydrogen gas, cyclohexene, cyclohexadiene, formic acid, ammoniumformate salts, etc.) at 0° C.-50° C. for 10-120 hr, then the liberatedfree hydroxyl group is acetylated in a basic organic solvent (e.g.pyridine, triethylamine, γ-lutidine, piperidine, N-methylmorpholine or amixture of these solvents, etc.) using an acetylating agent (e.g. aceticanhydride, acetyl chloride, and the like) at 0° C.-60° C. for 2-40 hr,which can lead to the compound represented by structural formula (30).Finally, in the reaction process (w), reaction of benzoyl (Bz) andacetyl groups (Ac) as the protective groups of the hydroxyl groups withan alkaline metal alkoxide or alkalineearthmetal alkoxide (e.g. sodiummethoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide,magnesium methoxide, calcium methoxide, and the like), or an alkalinemetal hydroxide or alkalineearthmetal hydroxide (e.g. sodium hydroxide,lithium hydroxide, potassium hydroxide, magnesium hydroxide, calciumhydroxide, and the like) in a protic solvent (e.g. water, methanol,ethanol, n-propanol, isopropanol, n-butanol, t-butanol or a mixture ofthese solvents, etc.) at 0° C.-40° C. for 2-48 hr can lead to thecompound represented by structural formula (δ) as2-fluorofucosyl-α-(1→4)-N-4-t-butylbenzoylglucosamine derivativeaccording to the present invention.

INDUSTRIAL APPLICATION

The derivatives of the present invention are2-fluorofucosyl-N-aroylglucosamine derivatives in which the hydroxylgroup at the 3- or 4-position of N-aroylglucosamine is substituted with2-fluorofucose. They are especially excellent in metabolic stabilityagainst decomposition enzymes such as fucosidase because they have the2-fluorofucose moiety. Further, as the N-aroylglucosamine moiety has thearoyl group, their selectin-adhesive-inhibition activity is superior.For example, they can provide derivatives that are excellent inmetabolic stability as well as highly selective inhibition of theadhesive process of leukocytes to selecting.

Therefore, they can suppress neutrophil (a kind of leukocyte)-dependentand selectin-dependent acute inflammation and the like, and are usefulas medicinal components for the purpose of the treatment, improvementand prevention of myocardial ischemic reperfusion disorder duringredisobliteration therapy such as percutaneous transluminal coronaryangioplasty (PTCA), acute respiratory distress syndrome (ARDS),inflammation, or thrombus formation accompanied with inflammnation,multiple sclerosis, bronchial asthma, rheumatism, autoimmune disease,chronic diseases such as allergic disease, diabetes, ophthalmopathy,psoriasis, and cancer. Further, it is possible to prepare the presentinventive derivatives with good reproductivity and in high yieldsaccording to the method for preparation of the present inventivederivatives. Furthermore, the present inventive intermediates of thederivatives are useful synthetic intermediates of the derivatives andtheir preparation methods, and it is possible to obtain theintermediates of the present inventive derivatives with goodreproductivity and in high yields according to the preparation method ofthe present inventive intermediates.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the remnant ratio of the sialyl Lewis Xderivatives at each time course after the addition of α-fucosidase.

EXAMPLES

The following examples are given to further illustrate the presentinvention. However, it should be understood that the present inventionis not limited by the following examples.

Reference Example

Object: synthesis of 2-(trimethylsilyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (e): hereinafter, abbreviated to compound (e)].

0.515 g (0.368 mmol) of 2-(trimethylsilyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranosidewas dissolved in 2.2 mL of anhydrous methanol, and 16 mg (0.296 m mol)ofsodium methoxide was added under an argon atmosphere, and the mixturewas stirred at room temperature for 2 hr. The reaction solution obtainedwas directly neutralized through a column of Amberlite IR120B (H⁺)(eluent:methanol). Subsequently, the residual which was obtained byconcentration of the combined eluates under reduced pressure wasdissolved in 4.7 mL of anhydrous dimethyl formamide, then, 0.35 mL (2.33mmol) of benzaldehyde dimethylacetal and 9 mg (0.047 mmol) ofp-toluenesulfonic acid monohydrate were added, and the mixture wasstirred at room temperature for 16 hr. The reaction solution obtainedwas passed through a layer of Amberlite IRA-410 (OH⁻) (eluent:methanol).Further, after concentrating the combined eluants under reducedpressure, the residual was purified through silica gel flashchromatography (eluent; hexane:ethyl acetate=2:1) to give 259 mg (53%yield) of 2-(trimethylsikyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[above compound (e)].

The analytical results of this compound are as follows:

C₈₀ H₈₇ NO₁₇ Si (mol. wt. 1362.7)

IR^(KBr) _(max) cm⁻¹ : 3475 (OH), 1715 (imide), 1090 (ether), 860, 840(Me₃ Si), 735, and 700 (Ph)

¹ H-NMR (CDCl₃ ; TMS):δ7.6-6.8 (m, 39H, Phthal+7Ph), 5.59 (s, 1H, PhCH),and 0.98 (m, 2H, CH₂ SiMe₃)

MS: m/z Found 1362.5821 (M+H); Calcd. 1362.5850 for C₈₀ H₈₇ NO₁₇ Si

Example 1

Object: synthesis of2-(trimethylsilyl)ethyl-O-(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)-O-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (10): hereinafter, abbreviated to compound(10)] 3.5 mg (0.075 mmol) of methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-β-L-fucopyranose represented bysaid structural formula (f) and 75 mg (0.055 mmol) of compound (e)obtained in the said Reference Example were dissolved in 2.3 mL ofanhydrous benzene and 0.4 g of activated molecular sieves (pore size 4Å) was added under an argon atmosphere. After stirring at roomtemperature for 16 hr and cooling up to about 7° C., 120 mg (0.465 mmol)of dimethyl(methylthio)sulfonium triflate (DMTST) was added and stirredat the same temperature for 2 hr. After cooling the reaction mixturedown to 4° C., 1.2 mL of methanol and then 0.4 mL of triethylamine wereadded, and stirred at the same temperature for 30 min. Then theinsoluble portion was separated by suction filtration and washed withdichloromethane. After washing the combined filtrate and the washingswith water, the solution was dried with sodium sulfate and concentratedunder reduced pressure. The residual was submitted to flashchromatography (eluent; n-hexane:ethyl acetate=4:1) to give 75 mg (80.6%yield) of the said compound (10).

The analytical results of this compound are as follows:

C₁₀₀ H₁₀₈ NO₂₀ FSi (mol. wt. 1691.1)

[α]_(D) ²³ =-41.6° (c 1.025, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3470 (NH), 1715 (imide), 1100 (ether), 860, 835(Me₃ Si), 735, and 700 (Ph)

¹ H-NMR (CDCl₃ ; TMS):δ7.8-6.8 (m, 49H, Phthal+9Ph), 5.57 (s, 1H, PhCH),4.89 (d, 1H, J₁,2 =4.1 Hz, H-1, fucose moiety), 0.98 (m, 2H, CH₂ SiMe₃),and 0.79 (d, 3H, J₅,6 =6.5 Hz, H-6, fucose moiety)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-207 (ddd, J_(F), 3H =9.4 Hz, J_(F), 1H =3.3Hz, 2-F)

MS: m/z Found 1690.7296 (M+H); Calcd. 1690.7308 for

Example 2

Object: synthesis of 2-(trimethylsilyl)ethylO-(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)-O-(4,6-O-benzylidene-2-deoxy-2-naphthamide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (11): heareinafter, abbreviated to compound(11)]

285 mg (0.169 mmol) of the compound (10) obtained in Example 1 wasdissolved in 26 mL of n-butanol under an argon atmosphere followed byadding 8.8 mL of ethylene diamine, and stirred at 82° C. for 20 hr.After concentrating under a reduced pressure at below 60° C., 48 mL ofpyridine, 750 mg (3.93 mmol) of 2-naphthoyl chloride and a further 25 mg(0.205 mmol) of N,N-dimethylaminopyridine were added to the residual,and the mixture was stirred at room temperature for 12 hr under an argonatmosphere. Then the reaction mixture was cooled down to 0° C. followedby adding 9 mL of methanol, and stirred at the same temperature for 2hr. After concentrating under a reduced pressure again, the residual waspurified by flash chromatography (eluent; n-hexane:ethyl acetate=5:2) togive 236 mg (81.7% yield) of the said compound (11).

The analytical results of this compound are as follows.

C₁₀₃ H₁₁₂ NO₁₉ FSi (mol. wt. 1715.1)

[α]_(D) ²³ =-41.2° (c 1.04, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3415 (NH), 1685, 1520 (amide), 1095 (ether), 860,835 (Me₃ Si), 735, and 695 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.0-6.8 (m, 52H, 2-Naphth+9Ph), 5.49 (s, 1H,PhCH), 5.05 (d, 1H, J₁,2 =3.8 Hz, H-1, fucosemoiety), 0.90 (m, 2H, CH₂SiMe₃), and 0.73 (d, J₅,6 =6.4 Hz, H-6, fucose moiety)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-207 (br ddd, J_(F), 2H =50 Hz, J_(F), 3H =8.9Hz, 2-F)

MS: m/z Found 1714.7660 (M+H); Calcd. 1714.7686 for C₁₀₃ H₁₁₂ NO₁₉ FSi

Example 3

Object: synthesis of 2-(trimethylsilyl)ethylO-(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)-O-(6-O-benzyl-2-deoxy-2-naphthamide-β-D-glucopyranosyl)-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula(12): hereinafter, abbreviated to compound(12)]. 46 mg (0.0268 mmol) of compound (11) obtained in Example 2 wasdissolved in 1.2 mL of anhydrous tetrahydrofuran, and 180 mg ofactivated molecular sieves (pore size 4 Å) was added under an argonatmosphere. After the mixture was stirred at room temperature for 1 hr,140 mg (2.22 mmol) of sodium cyanoborohydride was added at the sametemperature followed by cooling down to 0° C., and 2.8 mL (2.8 mmol) of1 M-hydrogenchloride-ether solution was dropped under an argonatmosphere. After raising the reaction temperature up to roomtemperature, stirring for 15 min, adding 5 mL of dichloromethane and 1mL of water, the insoluble portion was separated by filtration, and thenwashed with dichloromethane. The combined filtrate and washings werewashed with 2 M-aqueous hydrochloric acid, 5% aqueous sodium bicarbonateand satd. brine, and dried with sodium sulfate. After concentratingunder a reduced pressure, the residual was submitted to flashchromatography (eluent; n-hexane:ethyl acetate=2:1) to give 23 mg (50.0%yield) of said compound (12).

The analytical results of this compound are as follows:

C₁₀₃ H₁₁₄ NO₁₉ FSi (mol. wt. 1717.1)

[α]_(D) ²³ =-19.0° (c 0.51, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3700-3200 (OH, NH), 1670, 1495 (amide), 1070(ether), 860, 840 (Me₃ Si), 735, and 695 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.1-6.8 (m, 52H, 2-Naphth+9Ph), 5.81 (d, 1H,J=8.9 Hz, OH), 1.16 (d, 3H, J₅,6 =6.5 Hz, H-6, fucose moiety), and 0.97(m, 2H, CH₂ SiMe₃)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ207 (ddd, J_(F), 2H =51 Hz, J_(F), 3H =8.9 Hz,J_(F), 1H =2.8 Hz, 2-F)

MS: m/z Found 1716.7817 (M+H); Calcd. 1716.7661 for C₁₀₃ H₁₁₄ NO₁₉ FSi

Example 4

Object: synthesis of 2-(trimethylsilyl)ethylO-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-O-D-galactopyranosyl-(1→4)-O-[(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)]-O-(6-O-benzyl-2-deoxy-2-naphthamide-β-D-glucopyranosyl)-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (14): hereinafter abbreviated to compound (14)]

82.3 mg (0.048 mmol) of compound (12) obtained in Example 3 andO-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-1-thio-β-D-galactopyranoside[said structural formula (13)=said structural formula (g)] weredissolved in 3.6 mL of anhydrous dichloromethane and 500 mg of activatedmolecular sieves (pore size 4 Å) was added under an argon atmosphere.After stirring at room temperature for 2.5 hr, 72 mg (0.28 mmol) ofdimethyl(methylthio)sulfonium triflate (DMTST) was added and stirred atthe same temperature for 20 hr under an argon atmosphere. The reactionmixture was cooled in ice, then 0.4 mL of methanol and 0.2 mL oftrimethylamine were added, and stirred at the same temperature for 30min. After diluting with dichloromethane, filtration and washing, thecombined filtrate and the washings were washed with water. Further, thesolution was dried with sodium sulfate and concentrated under a reducedpressure. The residual obtained was submitted to flash chromatography(eluent; n-hexane:ethyl acetate=1:3) to give 72.7 mg (56.9% yield) ofsaid compound (14).

The analytical results of this compound are as follows:

C₁₅₀ H₁₆₃ N₂ O₃₉ FSi (mol. wt. 2665.0) [α]_(D) ²³ =-12.9° (c 0.52,chloroform)

IR^(KBr) _(max) cm⁻¹ : 3400 (NH), 1740, 1260 (ester), 1690, 1500(amide), 1070 (ether), 860, 805 (Me₃ Si), 735, and 715 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.3-7.0 (m, 67H, 2-Naphth+12Ph), 5.6 7 (m, 1H,H-8, sialic acid moiety), 5.56 (dd, 1H, J₁,2 =8.3 Hz, J₂, 3 =9.6 Hz,H-2, galactose moiety), 5. 35 (br. d, 1H, J₃, 4 =J₄, 5 =3.5 Hz, H-2,galactose moiety), 5.28 (dd, 1H, J₇, 8 =9.6 Hz, J₆, 7 =2.6 Hz, H-7,sialic acid moiety), 3.81 (s, 3H, OCH₃), 2.51 (dd, 1H, J_(3e), 3a =12.5Hz, J_(3e), 4 =4.5 Hz, H-3e, sialic acid moiety), 2.18, 2.00, 1.97, 1.84(4s, 12H, 4AcO), 1.56 (s, 3H, AcN), 1.11 (d, 3H, J₅, 6 =6.4 Hz, H-6,sialic acid moiety), and 1.01 (m, 2H, Me₃ SiCH₂ CH₂ O)

¹⁹ F-NMR (CDCl₃ ; CFCl₃): δ-208 (br ddd, J_(F), 2H =49 Hz, J_(F), 3H=7.50 Hz, 2-F).

MS: m/z Found 2665.0698 (M+H); Calcd. 2665.0736 for C₁₅₀ H₁₆₃ N₂ O₃₉ FSi

Example 5

Object: synthesis of 2-(trimethylsilyl)ethylO-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-.beta.-D-galactopyranosyl)-(1→4)-O-[(3,4-di-O-acetyl-2-deoxy-2-fluoro-.alpha.-L-fucopyranosyl-(1→3)3)]-O-[6-O-acetyl-2-deoxy-2-(5,6,7,8-tetrahydronaphthamide-β-D-glucopyranosyl)-(1→3)-O-(2,4,6-tri-O-acetyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside[said structural formula (15): hereinafter, abbreviated to compound(15)]. 25 mg (0.0093 mmol) of the compound (14) obtained in Example 4was dissolved in 4.2 mL of ethanol and 1.3 mL of acetic acid, and themixture was hydrogenated in hydrogen at atmospheric pressure in thepresence of 28 mg 10% palladium--carbon warming at 45° C. for 4 days.After filtrating this, the solvent was concentrated under a reducedpressure, 4 mL of pyridine and 2 mL of acetic anhydride were added tothe residual obtained, and stirred at room temperature for 20 hr. Afterthe solution was concentrated under a reduced pressure, the residualobtained was submitted to flash chromatography (eluent; n-hexane:ethylacetate=1:6) to give 12 mg (57.2% yield) of said compound (15).

The analytical results of this compound are as follows:

C₁₀₅ H₁₃₁ N₂ O₄₈ FSi (mol. wt. 2236.2)

[α]_(D) ²³ =-20.0° (c 0.43, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3380 (NH), 1750,1230 (ester), 1700, 1540 (amide),1070 (ether), 860, 840 (Me₃ Si), and 720 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.3-7.0 (m, 18H, 4HNaph+3Ph), 5.66 (m, 1H, H-8,sialic acid moiety), 4.46 (d, 1H, J₁, 2 =7.9 Hz, H-1, glucose moiety),3.80 (s, 3H, OCH₃), 2.83(br s, 4H, tetrahydronaphthalene moiety), 2.41(dd, 1H, J_(3a), 3e =12.6 Hz, J_(3e), 4 =4.5 Hz, H-3e, sialic acidmoiety), 2.14, 2.13, 2.09, 2.09, 2.08, 2.07, 2.05, 2.02, 2.01, 1.98,1.91, 1.90 (13 s, 39H, 13AcO), 1.56 (s, 3H, AcN), 1.08 (d, 3H, J₅, 6=6.5 Hz, H-6, fucose moiety), and 0.89 (m, 2H, Me₃ SiCH₂)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-208 (br dd, J_(F), 2H =50 Hz, J_(F), 3H =9.9Hz, 2-F)

MS: m/z Found 2236.7736 (M+H); Calcd. 2236.7709 for C₁₀₅ H₁₃₁ N₂ O₄₈ FSi

Example 6

Object: synthesis of 2-(trimethylsilyl)ethylO-(5-acetamide-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonicacid)-(2→3)-O-β-D-galactopyranosyl-(1→4)-O-[(2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)]-O-[(2-deoxy-2-(5,6,7,8-tetrahydronaphthamide-β-D-glucopyranosyl)-(1→3)-(O-β-D-galactopyranosyl)-(1→4)-β-D-glucopyranoside[said structural formula (α): hereinafter, abbreviated to compound (α)].12 mg (0.0053 mmol) of the compound (15) obtained in Example 5 wasdissolved in 1.0 mL of anhydrous methanol, then 10 mg (0.19 mmol) ofsodium methoxide was added at room temperature under an argonatmosphere, and stirred at 40° C. for 21 hr. After cooling at roomtemperature, 0.8 mL of water was added to the reaction mixture andstirred for 8 hr. Then the solution was passed through an AmberliteIR120 (H⁺) layer (eluent:methanol), and the residual concentrated undera reduced pressure was submitted to gel filtration column chromatography(eluent:methanol) using SephadexLH20 (15 g) to give 6.2 mg (85.0% yield)of compound (α).

The analytical results of this compound are as follows:

C₅₇ H₉₁ N₂ O₃₂ FSi (mol. wt. 1363.4)

[α]_(D) ²³ =-30.0° (c 0.50, methanol)

IR^(KBr) _(max) cm⁻¹ : 3700-3200 (OH, NH), 2930, 2850 (methyl,methylene), 1740 (carboxylic acid), 1635, 1555 (amide), and 1070 (ether)

¹ H-NMR (CD₃ OD; TMS): δ7.6-7.0 (m, 3H, 4HNaph), 5.26 (d, 1H, H-8, J₁, 2=3.8 Hz, H-1, fucose moiety), 2.88 (dd, 1H, J_(3a), 3e =12.7 Hz, J_(3e),4 =2.5 Hz, H-3e, sialic acid moiety), 2.80 (br s, 4H,tetrahydronaphthalene moiety), 2.02 (s, 3H, AcN), 1.17 (d, 3H, J₅, 6=6.5 Hz, H-6, fucose moiety), and 1.00 (m, 2H, Me₃ SiCH₂)

¹⁹ F-NMR (CD₃ OD; CFCl₃):δ-163 (br dd, J_(F), 2H =50 Hz, J_(F), 3H =10.8Hz, 2-F)

MS: m/z Found 1363.5837 (M+H); Calcd. 1363.5392 for C₅₇ H₉₁ N₂ O₃₂ FSi

Example 7

Object: synthesis of 2-(trimethylsilyl)ethylO-(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)-O-[4,6-O-benzylidene-2-deoxy-2-(4-t-butylbenzamide-β-D-glucopyranosyl)]-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (16): hereinafter, abbreviated to compound(16)].

291 mg (0.172 mmol) of the compound (10) obtained in Example 1 wasdissolved in 24 mL of n-butanol under an argon atmosphere, then 6 mL ofethylenediamine was added, stirred and heated at 8° C. for 20 hr. Then48 mL of pyridine, 0.8 mL (4.19 mmol) of 4-t-butylbenzoylchloride and 30mg (0.246 mmol) of N,N-dimethylaminopyridine were added to the residualobtained after concentrating below 60° C. under a reduced pressure, andthen stirred at room temperature under an argon atmosphere for 16 hr.After cooling down to 0° C., 9 mL of methanol was added and stirred atroom temperature for 3 hr. After concentration under a reduced pressureagain, the residue obtained was purified by flash chromatography(eluent; n-hexane:ethyl acetate=3:1) to give 280 mg (94.6% yield) ofcompound (16).

The analytical results of this compound are as follows:

C₁₀₃ H₁₁₈ NO₁₉ FSi (mol. wt. 1715.1) [α]_(D) ²³ =-39.1° (c 0.97,chloroform)

¹ H-NMR (CDCl₃ ; TMS): δ7.6-6.8 (m, 49H, t-BuBz+9Ph), 5.56 (s, 1H,PhCH), 5.07 (d, 1H, J₁, 2 =3.8 Hz, H-1, fucose moiety), 1.25 (s, 9H,t-Bu), 1.00 (m, 2H, CH₂ SiMe₃), and 0.79 (d, J₅, 6 =6.4 Hz, H-6, fucosemoiety)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-207 (ddd, J_(F), 2H =50 Hz, J_(F), 3H =9.4Hz, J_(F), 1H =2.7 Hz, 2-F)

MS: m/z Found 1721.8163 (M+H); Calcd. 1721.8177 for C₁₀₃ H₁₁₈ NO₁₉ FSi

Example 8

Object: synthesis of 2-(trimethylsilyl)ethylO-(3,4-di-O-benzyl-2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)-O-[6-O-benzyl-2-deoxy-2-(4-t-butylbenzamide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (17): hereinafter, abbreviated to compound(17)]. 214 mg (0.124 mmol) of compound (16) obtained in Example 7 wasdissolved in 10 mL of anhydrous tetrahydrofuran, and 900 mg of activatedmolecular sieves (pore size 4 Å) was added under an argon atmosphere.After the mixture was stirred at room temperature for 1 hr, 700 mg (11.1mmol) of sodium cyanoborohydride was added at the same temperature,cooled down to 0° C., then 13 mL (13 mmol) of 1 M-hydrogenchloride-ethersolution was dropped under an argon atmosphere. After raising thereaction temperature up to room temperature, this mixture was stirredfor 20 min, followed by adding 20 mL of dichloromethane and 15 ml ofwater, then the insoluble portion was separated by filtration, andwashed with dichloromethane. The combined filtrate and washings werewashed with 2 M-aqueous hydrochloric acid, 5% aqueous sodium bicarbonateand satd. brine, and dried with sodium sulfate.

After concentrating under a reduced pressure, the residual was submittedto flash chromatography (eluent; n-hexane:ethyl acetate=2:1) to give 186mg (86.8% yield) of said compound (17).

The analytical results of this compound are as follows:

C₁₀₃ H₁₂₀ NO₁₉ FSi (mol. wt. 1723.1)

[α]_(D) ²³ =-14.2° (c 1.05, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3430 (OH, NH), 1675, 1495 (amide), 1070 (ether),860, 840 (Me₃ Si), 735, and 700 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.1-6.8 (m, 49H, t-BuBz+9Ph), 5.71 (d, 1H, J=8.8Hz, OH), 5.05 (d, J₁, 2 =3.7 Hz, H-1, fucose moiety), 1.29 (s, 9H,t-Bu), 1.17 (d, 3H, J₅, 6 =6.5 Hz, H-6, fucose moiety), and 1.00 (m, 2H,CH₂ SiMe₃)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-207 (ddd, J_(F), 2H =51 Hz, J_(F), 3H =8.9Hz, J_(F), 1H =2.8 Hz, 2-F)

MS: m/z Found 1723.8320 (M+H); Calcd. 1723.8343 for C₁₀₃ H₁₂₀ NO₁₉ FSi

Example 9

Object: synthesis of 2-(trimethylsiiyl)ethylO-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-.beta.-D-galactopyranosyl-(1→4)-O-[(3,4-di-O-benzyl-2-deoxy-2-fluoro-.alpha.-L-fucopyranosyl)-(1→3)]-O-[6-O-benzyl-2-deoxy-2-(4-t-butylbenzamide)-β-D-glucopyranosyl]-(1→3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-glucopyranoside[said structural formula (18): hereinafter, abbreviated to compound(18)].

196 mg (0.114 mmol) of compound (17) obtained in Example 8 andmethyl-O-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-1-thio-β-D-galactopyranoside[said structural formula (13)] were dissolved in 6 mL of anhydrousdichloromethane and 500 mg of activated molecular sieves (pore size 4 Å)was added under an argon atmosphere. After stirring at room temperaturefor 12 hr, 165 mg (0.639 mmol) of dimethyl(methylthio)sulfonium triflate(DMTST) was added and stirred at the same temperature for 24 hr. Thereaction mixture was cooled in ice, then 0.6 mL of methanol and 0.3 mLof trimethylamine were added, and stirred at the same temperature for 30min. After diluting with dichloromethane, filtration and washing, thecombined filtrate and the washings were washed with aq. sodium carbonateand satd. brine. The solution was dried with sodium sulfate andconcentrated under a reduced pressure. The residual obtained wassubmitted to flash chromatography (eluent; n-hexane:ethyl acetate=1:3)to give 141 mg (46.4% yield) of the said compound (18).

The analytical results of this compound are as follows:

C₁₅₀ H₁₆₉ N₂ O₃₉ FSi (mol. wt. 2671.0)

[α]_(D) ²³ =-16.3°(c 0.895, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3400 (NH), 1740, 1270 (ester), 1670, 1500(amide), 1100 (ether), 860, 840 (Me₃ Si), 735, and 715 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.3-6.8 (m, 64H, t-BuBz+12 Ph), 5.70 (m, 1H,H-8, sialic acid moiety), 5.51 (dd, 1H, J₁, 2 =8.1 Hz, J₂, 3 =9.8 Hz,H-2, galactose moiety), 5.39 (br d, 1H, J₃, 4 =J₄, 5 =3.8 Hz, H-2,galactose moiety), 5.26 (dd, 1H, J₇, 8 =9.6 Hz, J₆, 7 =2.6 Hz, H-7,sialic acid moiety), 3.81 (s, 3H, OCH₃), 2.47 (dd, 1H, J_(3e), 3a =12.8Hz, J_(3e), 4 =4.5 Hz, H-3e, sialic acid moiety), 2.17, 1.98, 1.95, 1.83(4s, 12H, 4AcO), 1.56 (s, 3H, AcN), 1.25 (s, 9H, t-Bu), 1.14 (d, 3H, J₅,6 =6.4 Hz, H-6, sialic acid moiety), and 1.02 (m, 2H, Me₃ SiCH₂ CH₂ O)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-208 (br dd, J_(F), 2H =50 Hz, J_(F), 3H =7.1Hz, 2-F)

MS: m/z Found 2671.1168 (M+H); Calcd. 2671.1107 for C₁₅₀ H₁₆₉ N₂ O₃₉ FSi

Example 10

Object: synthesis of 2-(trimethylsilyl)ethylO-(methyl-5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonate)-(2→3)-O-(2,4,6-tri-O-benzoyl-.beta.-D-galactopyranosyl)-(1→4)-O-[(3,4-di-O-acetyl-2-deoxy-2-fluoro-.alpha.-L-fucopyranosyl)-(1→3)]-O-[6-O-acetyl-2-deoxy-2-(4-t-butylbenzamide)-β-D-glucopyranosyl]-(1→3)-O-(2,4,6-tri-O-acetyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside [said structural formula (19):hereinafter, abbreviated to compound (19)]. 138 mg (0.0516 mmol) ofcompound (18) obtained in Example 9 was dissolved in 18.3 mL of ethanoland 6.7 mL of acetic acid, and the mixture was catalyticallyhydrogenated by hydrogen at atmospheric pressure in the presence of 140mg of 10% palladium--carbon warming at 45° C. for 4 days. Afterfiltrating this, the solvent was concentrated under a reduced pressure,and 6 mL of pyridine and 4 mL of acetic anhydride were added to theresidual obtained and stirred at room temperature for 13 hr. After thesolution was concentrated under a reduced pressure, the residualobtained was submitted to flash chromatography (eluent; n-hexane:ethylacetate=1:6) to give 95.5 mg (82.7% yield) of said compound (19).

The analytical results of this compound are as follows:

C₁₀₅ H₁₃₃ N₂ O₄₈ FSi (mol. wt. 2238.2)

[α]_(D) ²⁴ =-23.4°(c 0.88, chloroform)

IR^(KBr) _(max) cm⁻¹ : 3400 (NH), 1750,1230 (ester), 1670, 1535 (amide),1070 (ether), 860, 840 (Me₃ Si), and 715 (Ph)

¹ H-NMR (CDCl₃ ; TMS): δ8.3-7.3 (m, 19H, t-BuBz+3Ph), 5.68 (m, 1H, H-8,sialic acid moiety), 4.42 (d, 1H, J₁, 2 =7.9 Hz, H-1, glucose moiety),3.80 (s, 3H, OCH₃), 2.42 (dd, 1H, J_(3a), 3e =12.6 Hz, J_(3e), 4 =4.5Hz, H-3e, sialic acid moiety), 2.14, 2.10, 2.10, 2.09, 2.08, 2.06, 2.02,2.01, 1.99, 1.92, 1.91, 1.79 (13 s, 39H, 13AcO), 1.58 (s, 3H, AcN), 1.34(s, 9H, t-Bu), 1.09 (d, 3H, J₅, 6 =6.5 Hz, H-6, fucose moiety), and 0.89(m, 2H, Me₃ SiCH₂)

¹⁹ F-NMR (CDCl₃ ; CFCl₃):δ-208 (br dd, J_(F), 2H =50 Hz, J_(F), 3H =9.4Hz, 2-F).

MS: m/z Found 2238.7893 (M+H); Calcd. 2238.7841 for C₁₀₅ H₁₃₃ N₂ O₄₈ FSi

Example 11

Object: synthesis of 2-(trimethylsilyl)ethylO-(5-acetamide-3,5-dideoxy-D-glycero-α-D-galacto-2-nunolopyranosylonicacid)-(2→3)-O-β-D-galactopyranosyl-(1→4)-O-[(2-deoxy-2-fluoro-α-L-fucopyranosyl)-(1→3)]-O-[(2-deoxy-2-(4-t-butylbenzamide)-β-D-glucopyranosyl)]-(1→3)-(O-β-D-galactopyranosyl)-(1→4)-β-D-glucopyranoside[the said structural formula (β): hereinafter, abbreviated to compound(β)]. 95.5 mg (0.0426 mmol) of compound (19) obtained in Example 10 wasdissolved in 6.5 mL of anhydrous methanol, then 40 mg (0.74 mmol) ofsodium methoxide was added at room temperature under an argonatmosphere, and stirred at 40° C. for 24 hr.

After cooling at room temperature, 0.9 mL of water was added to thereaction mixture and stirred for 8 hr. Then the solution was passedthrough an Amberlite IR120 (H⁺) layer (eluent:methanol), and theresidual concentrated under a reduced pressure was submitted to gelfiltration column chromatography (eluent:methanol) using SephadexLH20(25 g) to give 56.2 mg (96.6%) of compound (β).

The analytical results of this compound are as follows:

C₅₇ H₉₇ N₂ O₃₂ FSi (mol. wt. 1365.4)

[α]_(D) ²³ =-30.4°(c 0.50, methanol)

IR^(KBr) _(max) cm⁻¹ : 3700-3200 (OH, NH), 2950 (methyl), 1740(carboxylic acid), 1630, 1550 (amide), and 1070 (ether)

¹ H-NMR (CD₃ OD; TMS): δ7.8-7.4 (dd, 4H, t-BuBz), 5.26 (d, 1H, H-8, J₁,2 =4.0 Hz, H-1, fucose moiety), 4.27 (d, 1H, J₁, 2 =7.8 Hz, H-1, glucosemoiety), 2.88 (dd, 1H, J_(3a), 3e =12.7 Hz, J_(3e), 4 =2.9 Hz, H-3e,sialic acid moiety), 2.01 (s, 3H, AcN), 1.35 (s, 9H, t-Bu), 1.16 (d, 3H,J₅, 6 =6.5 Hz, H-6, fucose moiety), and 1.00 (m, 2H, Me₃ SiCH₂)

¹⁹ F-NMR (CD₃ OD; CFCl₃):δ-162 (br dd, J_(F), 2H =51 Hz, J_(F), 3H =10.8Hz, 2-F).

MS: m/z Found 1365.5543 (M+H); Calcd. 1365.5560 for C₅₇ H₉₇ N₂ O₃₂ Fsi

Found 1387.5363 (M+Na); Calcd. 1387.5384

Evaluation of Metabolic Stability

The metabolic stability of various sialyl Lewis X derivatives toα-fucosidase was assayed. The various sialyl Lewis X derivatives whichwere used in Example [(2F-Fuc-t-Bu) SLcXOSE], Comparative Example 1(SLeX Ganglioside), and Comparative Example 2 [(2F-Fuc) SLeXGanglioside] are shown in the following structural formulas. Herein, thecompound used in the present Example is the compound represented by saidstructural formula (β) obtained in said Example 11. ##STR48## After 30mmol of each sialyl Lewis X derivative was dissolved in 0.1 mL of dist.water, 0.1 mL of ammonium sulfate suspension of α-fucosidase (made byWako Chemicals: 2 units or more/mg protein) was added to this solutionat 28° C., then the reaction solution was charged on a silica gel TLCplate 5715 (made by Merck Company) at every reaction time course. Afterdeveloping up to 2 cm using developing solvents (n-butanol:aceticacid:water=8:5:4), this was soaked in an aqueous solution of molybdenumphosphate/phosphoric acid/sulfuric acid mixture, and heated to color.The Rf values (moving ratio) on the TLC plate of products decomposed byα-fucosidase and each sialyl Lewis X derivative (substrate) were asfollows.

Comparative Example 1

substrate (SleX Ganglioside): Rf=0.75,

decomposed products: Rf=0.20

Comparative Example 2

substrate [(2F-Fuc) SleX Ganglioside]: Rf=0.75,

decomposed products: Rf=0.20

Example

substrate [(2-Fuc-t-bu) SLcXOSE]: Rf=0.70,

decomposed products: Rf=0.20

Namely, it was found that the Rf of the decomposed products all showedthe same value (0.20). Further, it was confirmed from the mass spectrumthat each sialyl Lewis X derivative is decomposed by α-fucosidase, andthe corresponding derivatives from which the fucose moiety was removedwere produced as respective decomposed products. Further, as shown infollowing Table 1, the residual rates of the individual sialyl Lewis Xderivatives were calculated from each spot area (hereinafter, sometimesreferred to merely as the area) after each reaction time course asfollows. Herein, each area was measured using a densitometer (software:VILBER LOURMAT BIOID V 6.31a): Residual rate of sialyl Lewis Xderivative=(substrate area)/(total area of substrate area plusdecomposed product area). The following Table 1 shows the obtained spotareas of individual sialyl Lewis X derivatives for each time.

Further, FIG. 1 shows the graphed residual rates of the individualsialyl Lewis X derivatives obtained from these spot areas.

                  TABLE 1                                                         ______________________________________                                                Spot Area (cm.sup.2)                                                  TimeCourse                                                                              Comparative  Comparative                                              (min) Example 1 Example 2 Example                                           ______________________________________                                        0         1.0          1.0       1.0                                            0.5 0.0 * 0.36 --                                                             1.0 --  0.30 0.73                                                             2.0 -- -- 0.44                                                              ______________________________________                                         Here, * indicates that the color on the TLC completely disappeared.      

From FIG. 1, it is clear that the compounds in the present Example areexcellent in stability against α-fucosidase. The natural type sialylLewis X ganglioside (Comparative Example 1: SLeX Ganglioside) showsrapid decomposition by α-fucosidase, while the sialyl Lewis Xganglioside (comparative Example 2: (2F-Fuc) SLeX Ganglioside) in whichthe hydroxy group at 2-position of fucose is substituted with a fluorineatom exhibits a weak resistance to decomposition by α-fucosidase, and isbetter in metabolic stability.

It has been found that the compound of the present Example [structuralformula (β):(2F-Fuc-t-Bu) SLcXOSE] is strongly resistant todecomposition reaction by α-fucosidase. This is because the compound ofthe present Example is not easily decomposed by α-fucosidase comparedwith other derivatives, and is excellent in metabolic stability. Fromthis result, it is expected to be capable of retaining sufficientselectin-adhesive-inhibition activity.

What is claimed is:
 1. 2-Fluorofucosyl-N-aroylglucosamine derivativesrepresented by the following general formula (1): ##STR49## wherein Xand Y in said general formula (1) are groups represented by followinggeneral formulas (A) or (B), if X is general formula (A), Y is generalformula (B), and if X is general formula (B), Y is general formula (A)##STR50## herein, in said general formula (A), R is a hydrogen atom, aprotective group of the hydroxyl group, phosphate residue, sulfateresidue, or a sialyl group represented by the following general formula(a), ##STR51## wherein R⁶ in the above general formula (a) shows ahydrogen atom, sodium atom or C1-10 alkyl group; R⁷ shows a hydrogenatom, C1-10 alkanoyl group or C7-15 aroyl group; R⁸ shows an acetylgroup, hydroxyacetyl group or C1-10 alkanoyloxyacetyl group), further,in the above general formula (1), R¹ is a hydrogen atom, hydroxyl group,C1-10 alkanoyloxy group having no substituent or having one or moresubstituents, C7-15 aroyloxy group, arylthio group having no substituentor having one or more substituents, C1-18 alkoxy group, branched longchain alkoxy group, arylmethoxy group having no substituent or havingone or more substituents, or 2-trisilylethoxy group having C1-4 alkylgroup or phenyl group, or a group represented by following generalformulas (b) or (c), ##STR52## wherein R⁹ in the above general formulas(b) and (c) shows a hydrogen atom, C1-10 alkanoyl group, C7-15 aroylgroup or phenylmethoxy group having no substituent or havingsubstituents; R¹⁰ shows a hydrogen atom, hydroxyl group,2-trisilylethoxy group having C1-4 alkyl group or phenyl group, C1-30alkoxy group, or a group represented by following general formula (d);and R¹¹ shows a hydrogen atom or --O--C(═NH)CCl₃, ##STR53## wherein R¹²in the above general formula (d) shows a hydrogen atom or benzoyl group;R¹³ shows an azide, amine or sphingosine represented by NHCO R¹⁴ (R¹⁴ isa C15-25 alkyl group); R¹¹ shows a hydrogen atom or --O--C(═NH)CCl₃, andin the above general formula (1), (A) and (B), R², R³ and R⁴ are ahydrogen atom, C1-10 alkanoyl group, C7-15 aroyl group, or phenylmethylgroup having no substituent or having substituents (wherein at least twoof R², R³ and R⁴ may be the same or different from each other) and R₅shows an aroyl group having no substituent or having substituents. 2.The 2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 1represented by the following general formula (2): ##STR54## (wherein R,R¹ and R⁵ in said general formula (2) are the same as described above).3. The 2-fluorofucosyl-N-aroylglucosamine derivatives as claimed inclaim 1 represented by the following general formula (3): ##STR55##(wherein R, R¹ and R⁵ in said general formula (3) are the same asdescribed above).
 4. The 2-fluorofucosyl-N-aroylglucosamine derivativesas claimed in claim 1 represented by the following structural formula(α): ##STR56##
 5. The 2-fluorofucosyl-N-aroylglucosamine derivatives asclaimed in claim 1 represented by the following structural of formula(β):
 6. The 2-fluorofucosyl-N-aroylglucosamine derivatives as claimed inclaim 1 represented by the following structural formula (γ):
 7. The2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 1represented by the following structural formula (δ):
 8. A method forpreparing the 2-fluorofucosyl-N-aroylglucosamine derivatives wherein acompound represented by the following general formulas (A') and (B') andan aroylglucosamine derivative represented by the following generalformula (C') are used when preparing the2-fluorofucosyl-N-aroylglucosamine derivatives represented by saidgeneral formula (1), (wherein R, R¹, R², R³, R⁴ and R⁵ in said generalformulas (A'), (B') and (C') are the same as described above; R¹⁷, R¹⁸,R¹⁹ and R²⁰ are reactive groups, respectively; and R¹⁷ shows reactivitywith R¹⁹ or R²⁰ ; and R¹⁸ shows reactivity with R¹⁹ or R²⁰).
 9. Themethod for preparing the 2-fluorofucosyl-N-aroylglucosamine derivativeas claimed in claim 8 comprises processes of: synthesizing anintermediate of the 2-fluorofucosyl-N-aroylglucosamine derivativethrough reaction of the aroylglucosamine derivative of said generalformula (C') with 2-fluorofucose of said general formula (B'); reactingsaid intermediate with a galactose derivative of said general formula(A'); and hydrogenation, when preparing the2-fluorofucosyl-N-aroylglucosamine derivatives represented by saidgeneral formula (2).
 10. The method for preparing the2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 8comprises processes of: synthesizing an intermediate of the2-fluorofucosyl-N-aroylglucosamine derivative through reaction of thearoylglucosamine derivative of said general formula (C') with agalactose derivative of said general formula (A'); reacting saidintermediate with 2-fluorofucose of said general formula (B'); andhydrogenation, when preparing the 2-fluorofucosyl-N-aroylglucosaminederivatives represented by said general formula (3).
 11. The method forpreparing the 2-fluorofucosyl-N-aroylglucosamine derivatives as claimedin claim 8 comprises processes through: reacting 2-(trimethylsiiyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-o-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranosiderepresented by the following structural formula (e) with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bythe following structural formula (f); introducing a 2-naphthamide groupas a substituent instead of said phthalimide group; cleaving saidbenzylidene group; reacting the obtained intermediate of2-fluorofucosyl-N-aroylglucosamine derivative with a sialylgalactosederivative represented by the following structural formula (g) tointroduce as a substituent into said cleavage site; hydrogenationreduction; acetylation; and hydrolysis, when preparing the2-fluorofucosyl-N-aroylglucosamine derivatives represented by saidstructural formula (α), ##STR57##
 12. The method for preparing the2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 8comprises processes through: reacting 2-(trimethylsilyl)ethylO-(4,6-O-benzylidene-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranosiderepresented by said structural formula (e) with methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bysaid structural formula (f); introducing a 4-t-butylbenzamide group as asubstituent instead of said phthalimide group; cleaving said benzylidenegroup; reacting the obtained intermediate of2-fluorofucosyl-N-aroylglucosamine derivative with a sialylgalactosederivative represented by said structural formula (g) to introduce as asubstituent into said cleavage site; hydrogenation reduction;acetylation; and hydrolysis, when preparing the2-fluorofucosyl-N-aroylglucosamine derivative represented by saidstructural formula (β).
 13. The method for preparing the2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 8comprises processes through: introducing a 2-naphthamide group as asubstituent instead of said phthalimide group in 2-(trimethylsilyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranosiderepresented by the following structural formula (h); converting saidO-acetyl groups into hydroxyl groups by hydrolysis; forming abenzylidene group by dehydrating condensation to said hydroxyl groups;cleaving the benzylidene group; reacting the obtained intermediate of2-fluorofucosyl-N-aroylglucosamine derivative with a sialylgalactosederivative represented by said structural formula (g) to introduce as asubstituent into said cleavage site; reacting methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bysaid structural formula (f); hydrogenation reduction; acetylation; andhydrolysis, when preparing the 2-fluorofucosyl-N-aroylglucosaminederivatives represented by said structural formula (γ),
 14. The methodfor preparing the 2-fluorofucosyl-N-aroylglucosamine derivatives asclaimed in claim 8 comprises processes through: introducing a4-t-butylbenzamide group as a substituent instead of said phthalimidegroup in 2-(trimethylsilyl)ethylO-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimide-β-D-glucopyranosyl)-(1.fwdarw.3)-O-(2,4,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranosiderepresented by said structural formula (h); converting said O-acetylgroups into hydroxyl groups by hydrolysis; forming a benzylidene groupby dehydrating condensation to said hydroxyl groups; cleaving thebenzylidene group; reacting the obtained intermediate of2-fluorofucosyl-N-aroylglucosamine derivative with a sialylgalactosederivative represented by said structural formula (g) to introduce as asubstituent into said cleavage site; reacting methyl3,4-di-O-benzyl-2-deoxy-2-fluoro-1-thio-L-fucopyranoside represented bysaid structural formula (f); hydrogenation reduction; acetylation; andhydrolysis, when preparing the 2-fluorofucosyl-N-aroylglucosaminederivatives represented by said structural formula (δ). 15.Intermediates of 2-fluorofucosyl-N-aroylglucosamine derivativesrepresented by the following general formula (4), (wherein R¹⁵ shows aphenyl group having no substituent or having substituents; and R¹⁶ showsan aroyl group having no substituent or having substituents).
 16. Theintermediates of the 2-fluorofucosyl-N-aroylglucosamine derivatives asclaimed in claim 15 wherein said R¹⁶ is one group selected from thegroups consisting of a phthalimide ring group, a 2-naphthoylamide groupand a 4-t-butylbenzoylamide group.
 17. The intermediates of the2-fluorofucosyl-N-aroylglucosamine derivatives represented by thefollowing general formula (5): ##STR58## (wherein R¹⁶ is the same asclaimed in claim 15).
 18. The intermediates of the2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 17wherein said R¹⁶ is one group selected from the groups consisting of aphthalimide ring group, a 2-naphthoylamide group and a4-t-butylbenzoylamide group.
 19. The method for preparing theintermediates of 2-fluorofucosyl-N-aroylglucosamine derivativescomprises reaction of the aroylglucosamine derivative represented by thefollowing general formula (i) with the compound represented by generalformula (B'), when preparing the intermediates of2-fluorofucosyl-N-aroylglucosamine derivatives represented by generalformula (4), ##STR59##20.
 20. The method for preparing the intermediatesof 2-fluorofucosyl-N-aroylglucosamine derivatives as claimed in claim 19wherein said R¹⁶ in said general formula (i) is one group selected fromthe groups consisting of a phthalimide ring group, a 2-naphthoylamidegroup and a 4-t-butylbenzoylamide group.
 21. The method for preparingthe intermediates of 2-fluorofucosyl-N-aroylglucosamine derivativescomprises cleavage of a benzylidene ring group in the intermediates of2-fluorofucosyl-N-aroylglucosamine derivatives represented by saidgeneral formula (4) as claimed in claim 15, when preparing theintermediates of 2-fluorofucosyl-N-aroylglucosamine derivativesrepresented by general formula (5).
 22. The method for preparing theintermediates of 2-fluorofucosyl-N-aroylglucosamine derivatives asclaimed in claim 21 wherein said R¹⁶ in said general formula (5) is onegroup selected from the groups consisting of a phthalimide ring group, a2-naphthoylamide group and a 4-t-butylbenzoylamide group.